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Deng W, Wang Y, Wang J, Su Y, Li M, Qu K, Wang Y, Li M. Leveraging Vitamin C to Augment Nanoenabled Photothermal Immunotherapy. ACS NANO 2025; 19:12982-12995. [PMID: 40138545 DOI: 10.1021/acsnano.4c17080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
Photothermal immunotherapy (PTI) is valuable for precise tumor targeting and immune activation. However, its efficacy is hindered by insufficient immune response, elevated antioxidant levels within tumor, and intrinsic tumor resistance mechanisms. This study introduces Vitamin C (VC), a widely available dietary nutrient, as an effective enhancer for PTI. High-dose VC induces oxidative imbalance in tumor cells, making them more susceptible to nanoenabled near-infrared-II photothermal therapy (NIR-II PTT) with the photosensitizer IR1080. The combination of VC and NIR-II PTT significantly amplifies antitumor immunity by upregulating CXCL16 expression and promoting CXCR6+ T cell infiltration. Clinical data reveal that higher CXCL16 and CXCR6 levels in human tumors correlate with improved survival and T cell infiltration, underscoring the translational potential of this approach. This study positions VC as a safe, accessible, and cost-effective dietary enhancer for PTI, reshaping the role of dietary nutrients in cancer therapy and offering a strategy for overcoming treatment resistance.
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Affiliation(s)
- Wuxian Deng
- Department of Radiology, the First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001 Anhui, China
- National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027 Anhui, China
| | - Yiyuan Wang
- Department of Radiology, the First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001 Anhui, China
- National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027 Anhui, China
| | - Junyu Wang
- National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027 Anhui, China
| | - Yitan Su
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230601 Anhui, China
| | - Mingyang Li
- National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027 Anhui, China
| | - Kun Qu
- National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027 Anhui, China
| | - Yucai Wang
- Department of Radiology, the First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001 Anhui, China
- National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027 Anhui, China
- Center for Advanced Interdisciplinary Science and Biomedicine of IHM, Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, 230601 Anhui, China
- Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, 230027 Anhui, China
| | - Min Li
- Department of Radiology, the First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001 Anhui, China
- National Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230027 Anhui, China
- Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, 230027 Anhui, China
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Alberts A, Moldoveanu ET, Niculescu AG, Grumezescu AM. Vitamin C: A Comprehensive Review of Its Role in Health, Disease Prevention, and Therapeutic Potential. Molecules 2025; 30:748. [PMID: 39942850 PMCID: PMC11820684 DOI: 10.3390/molecules30030748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/28/2025] [Accepted: 02/04/2025] [Indexed: 02/16/2025] Open
Abstract
Since Albert Szent-Györgyi discovered it and it became used in treating scurvy, vitamin C has attracted interest in many studies due to its unique properties. It is an important cofactor in the synthesis of collagen and hormones, and it is involved in immunity, iron absorption, and processes requiring antioxidants. Thus, this review aims to emphasize the importance and usefulness of vitamin C in improving quality of life and preventing various diseases (e.g., chronic diseases, cardiovascular diseases, cancer) but also for its use in treatments against infections, neurodegenerative diseases, and cancer. Although the studies presented provide essential information about the properties of VIC and its beneficial effect on health, some studies contradict these theories. In this respect, further studies on larger samples and over a longer period are needed to demonstrate the therapeutic potential of this nutrient. However, VIC remains a necessary vitamin that should be consumed daily to maintain optimal health and prevent deficiencies that can lead to scurvy and its associated complications.
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Affiliation(s)
- Adina Alberts
- Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Elena-Theodora Moldoveanu
- National University of Science and Technology Politehnica Bucharest, 011061 Bucharest, Romania; (E.-T.M.); (A.-G.N.)
| | - Adelina-Gabriela Niculescu
- National University of Science and Technology Politehnica Bucharest, 011061 Bucharest, Romania; (E.-T.M.); (A.-G.N.)
- Research Institute of the University of Bucharest—ICUB, University of Bucharest, 050657 Bucharest, Romania
| | - Alexandru Mihai Grumezescu
- National University of Science and Technology Politehnica Bucharest, 011061 Bucharest, Romania; (E.-T.M.); (A.-G.N.)
- Research Institute of the University of Bucharest—ICUB, University of Bucharest, 050657 Bucharest, Romania
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3
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Münzel T, Daiber A, Prochaska J. How quitting, switching to e-cigarettes, or sticking to smoking shapes cardiovascular outcomes after percutaneous coronary intervention. Eur Heart J 2025; 46:96-98. [PMID: 39523565 DOI: 10.1093/eurheartj/ehae756] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2024] Open
Affiliation(s)
- Thomas Münzel
- University Medical Center Mainz, Department of Cardiology, Johannes Gutenberg University, Langenbeckstrasse 1, D-55131 Mainz, Germany
| | - Andreas Daiber
- University Medical Center Mainz, Department of Cardiology, Johannes Gutenberg University, Langenbeckstrasse 1, D-55131 Mainz, Germany
| | - Jürgen Prochaska
- University Medical Center Mainz, Department of Cardiology, Johannes Gutenberg University, Langenbeckstrasse 1, D-55131 Mainz, Germany
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Münzel T, Kuntic M, Stamm P, Daiber A. E-cigarettes and vaping, new spotlight on smoking as an old cardiovascular risk factor? Herz 2024; 49:441-447. [PMID: 39499272 DOI: 10.1007/s00059-024-05278-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/25/2024] [Indexed: 11/07/2024]
Abstract
Smoking is one of the leading causes of chronic non-communicable diseases and a significant risk factor for cardiovascular and respiratory diseases. While global tobacco consumption has decreased over the past two decades, the use of e‑cigarettes and water pipes (shisha) has surged at an alarming rate, particularly among younger individuals. E‑cigarettes do not offer a completely risk-free alternative to traditional cigarettes, as the vast array of flavors and ease of use contribute to a growing number of dependent users. Furthermore, they are not necessarily effective in overcoming nicotine addiction. This contribution provides an overview of the cardiovascular health impacts associated with shisha smoking and e‑cigarette vaping, with a particular emphasis on the detrimental effects on endothelial function. The harmful biological effects of the toxic substances in these products, especially oxidative stress and inflammatory responses, are also discussed. Finally, the current state of recommendations, legal regulations, and commercial advertising are summarized.
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Affiliation(s)
- Thomas Münzel
- Department of Cardiology, Johannes Gutenberg University, University Medical Center Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.
| | - Marin Kuntic
- Department of Cardiology, Johannes Gutenberg University, University Medical Center Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Paul Stamm
- Department of Cardiology, Johannes Gutenberg University, University Medical Center Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Andreas Daiber
- Department of Cardiology, Johannes Gutenberg University, University Medical Center Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
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5
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Kuntic M, Hahad O, Al-Kindi S, Oelze M, Lelieveld J, Daiber A, Münzel T. Pathomechanistic Synergy Between Particulate Matter and Traffic Noise-Induced Cardiovascular Damage and the Classical Risk Factor Hypertension. Antioxid Redox Signal 2024. [PMID: 38874533 DOI: 10.1089/ars.2024.0659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/15/2024]
Affiliation(s)
- Marin Kuntic
- Department of Cardiology 1, Medical Center of the Johannes Gutenberg University, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Mainz, Germany
| | - Omar Hahad
- Department of Cardiology 1, Medical Center of the Johannes Gutenberg University, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Mainz, Germany
| | - Sadeer Al-Kindi
- Cardiovascular Prevention & Wellness and Center for CV Computational & Precision Health, Houston Methodist DeBakey Heart & Vascular Center, Houston, Texas, USA
| | - Matthias Oelze
- Department of Cardiology 1, Medical Center of the Johannes Gutenberg University, Mainz, Germany
| | - Jos Lelieveld
- Max Planck Institute for Chemistry, Atmospheric Chemistry, Mainz, Germany
| | - Andreas Daiber
- Department of Cardiology 1, Medical Center of the Johannes Gutenberg University, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Mainz, Germany
| | - Thomas Münzel
- Department of Cardiology 1, Medical Center of the Johannes Gutenberg University, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Mainz, Germany
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Ishida M, Sakai C, Kobayashi Y, Ishida T. Cigarette Smoking and Atherosclerotic Cardiovascular Disease. J Atheroscler Thromb 2024; 31:189-200. [PMID: 38220184 PMCID: PMC10918046 DOI: 10.5551/jat.rv22015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 12/01/2023] [Indexed: 01/16/2024] Open
Abstract
The detrimental effects of cigarette smoking on cardiovascular health, particularly atherosclerosis and thrombosis, are well established, and more detailed mechanisms continue to emerge. As the fundamental pathophysiology of the adverse effects of smoking, endothelial dysfunction, inflammation, and thrombosis are considered to be particularly important. Cigarette smoke induces endothelial dysfunction, leading to impaired vascular dilation and hemostasis regulation. Factors contributing to endothelial dysfunction include reduced bioavailability of nitric oxide, increased levels of superoxide anion, and endothelin release. Chronic inflammation of the vascular wall is a central pathogenesis of smoking-induced atherosclerosis. Smoking systemically elevates inflammatory markers and induces the expression of adhesion molecules and cytokines in various tissues. Pattern recognition receptors and damage-associated molecular patterns play crucial roles in the mechanism underlying smoking-induced inflammation. Smoking-induced DNA damage and activation of innate immunity, such as the NLRP3 inflammasome, cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, and Toll-like receptor 9, are shown to amplify inflammatory cytokine expression. Cigarette smoke-induced oxidative stress and inflammation influence platelet adhesion, aggregation, and coagulation via adhesion molecule upregulation. Furthermore, it affects the coagulation cascade and fibrinolysis balance, causing thrombus formation. Matrix metalloproteinases contribute to plaque vulnerability and atherothrombotic events. The impact of smoking on inflammatory cells and adhesion molecules further intensifies the risk of atherothrombosis. Collectively, exposure to cigarette smoke exerts profound effects on endothelial function, inflammation, and thrombosis, contributing to the development and progression of atherosclerosis and atherothrombotic cardiovascular diseases. Understanding these intricate mechanisms highlights the urgent need for smoking cessation to protect cardiovascular health. This comprehensive review investigates the multifaceted mechanisms through which smoking contributes to these life-threatening conditions.
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Affiliation(s)
- Mari Ishida
- Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Chiemi Sakai
- Department of Cardiovascular Physiology and Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yusuke Kobayashi
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takafumi Ishida
- Department of Cardiovascular Medicine, Fukushima Medical University, Fukushima, Japan
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Higashi Y. Smoking cessation and vascular endothelial function. Hypertens Res 2023; 46:2670-2678. [PMID: 37828134 PMCID: PMC10695829 DOI: 10.1038/s41440-023-01455-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2023] [Revised: 09/01/2023] [Accepted: 09/07/2023] [Indexed: 10/14/2023]
Abstract
Smoking is associated with vascular endothelial dysfunction. It is thought that smoking impairs vascular endothelial function through a decrease in nitric oxide bioavailability induced by activation of oxidative stress and inflammation. Endothelial dysfunction can be improved or augmented by appropriate interventions including pharmacotherapy, administration of supplements and lifestyle modifications. Although there have not been many studies, the effects of smoking cessation on endothelial function have been shown. In those studies, it was shown that smoking cessation does not always have a positive effect on vascular endothelial function. In this review, I will focus on the role of smoking in endothelial function and the effects of smoking cessation on endothelial function. Smoking impairs vascular endothelial function and leads to atherosclerosis. Smoking cessation is expected to improve vascular endothelial function. Effects of smoking cessation on endothelial function are not always consistent. Further studies are needed to determine whether smoking cessation directly improves endothelial function. NO indicates nitric oxide.
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Affiliation(s)
- Yukihito Higashi
- Department of Regenerative Medicine, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
- Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan.
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Rushing BR, Thessen AE, Soliman GA, Ramesh A, Sumner SCJ. The Exposome and Nutritional Pharmacology and Toxicology: A New Application for Metabolomics. EXPOSOME 2023; 3:osad008. [PMID: 38766521 PMCID: PMC11101153 DOI: 10.1093/exposome/osad008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/22/2024]
Abstract
The exposome refers to all of the internal and external life-long exposures that an individual experiences. These exposures, either acute or chronic, are associated with changes in metabolism that will positively or negatively influence the health and well-being of individuals. Nutrients and other dietary compounds modulate similar biochemical processes and have the potential in some cases to counteract the negative effects of exposures or enhance their beneficial effects. We present herein the concept of Nutritional Pharmacology/Toxicology which uses high-information metabolomics workflows to identify metabolic targets associated with exposures. Using this information, nutritional interventions can be designed toward those targets to mitigate adverse effects or enhance positive effects. We also discuss the potential for this approach in precision nutrition where nutrients/diet can be used to target gene-environment interactions and other subpopulation characteristics. Deriving these "nutrient cocktails" presents an opportunity to modify the effects of exposures for more beneficial outcomes in public health.
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Affiliation(s)
- Blake R. Rushing
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Anne E Thessen
- Department of Biomedical Informatics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Ghada A. Soliman
- Department of Environmental, Occupational and Geospatial Health Sciences, City University of New York-Graduate School of Public Health and Health Policy, New York, NY, USA
| | - Aramandla Ramesh
- Department of Biochemistry, Cancer Biology, Neuroscience & Pharmacology, Meharry Medical College, Nashville, TN, USA
| | - Susan CJ Sumner
- Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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9
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Wölkart G, Kollau A, Russwurm M, Koesling D, Schrammel A, Mayer B. Varied effects of tobacco smoke and e-cigarette vapor suggest that nicotine does not affect endothelium-dependent relaxation and nitric oxide signaling. Sci Rep 2023; 13:15833. [PMID: 37739972 PMCID: PMC10517138 DOI: 10.1038/s41598-023-42750-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2023] [Accepted: 09/14/2023] [Indexed: 09/24/2023] Open
Abstract
Chronic smoking causes dysfunction of vascular endothelial cells, evident as a reduction of flow-mediated dilation in smokers, but the role of nicotine is still controversial. Given the increasing use of e-cigarettes and other nicotine products, it appears essential to clarify this issue. We studied extracts from cigarette smoke (CSE) and vapor from e-cigarettes (EVE) and heated tobacco (HTE) for their effects on vascular relaxation, endothelial nitric oxide signaling, and the activity of soluble guanylyl cyclase. The average nicotine concentrations of CSE, EVE, and HTE were 164, 800, and 85 µM, respectively. At a dilution of 1:3, CSE almost entirely inhibited the relaxation of rat aortas and porcine coronary arteries to acetylcholine and bradykinin, respectively, while undiluted EVE, with a 15-fold higher nicotine concentration, had no significant effect. With about 50% inhibition at 1:2 dilution, the effect of HTE was between CSE and EVE. Neither extract affected endothelium-independent relaxation to an NO donor. At the dilutions tested, CSE was not toxic to cultured endothelial cells but, in contrast to EVE, impaired NO signaling and inhibited NO stimulation of soluble guanylyl cyclase. Our results demonstrate that nicotine does not mediate the impaired endothelium-dependent vascular relaxation caused by smoking.
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Affiliation(s)
- Gerald Wölkart
- Department of Pharmacology and Toxicology, Institute of Pharmaceutical Sciences, Universität Graz, Humboldtstraße 46, 8010, Graz, Austria
| | - Alexander Kollau
- Department of Pharmacology and Toxicology, Institute of Pharmaceutical Sciences, Universität Graz, Humboldtstraße 46, 8010, Graz, Austria
| | - Michael Russwurm
- Department of Pharmacology and Toxicology, Ruhr-Universität Bochum, MA N1-39, 44780, Bochum, Germany
| | - Doris Koesling
- Department of Pharmacology and Toxicology, Ruhr-Universität Bochum, MA N1-39, 44780, Bochum, Germany
| | - Astrid Schrammel
- Department of Pharmacology and Toxicology, Institute of Pharmaceutical Sciences, Universität Graz, Humboldtstraße 46, 8010, Graz, Austria
| | - Bernd Mayer
- Department of Pharmacology and Toxicology, Institute of Pharmaceutical Sciences, Universität Graz, Humboldtstraße 46, 8010, Graz, Austria.
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Daiber A, Kuntic M, Oelze M, Hahad O, Münzel T. E-cigarette effects on vascular function in animals and humans. Pflugers Arch 2023:10.1007/s00424-023-02813-z. [PMID: 37084087 DOI: 10.1007/s00424-023-02813-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Revised: 04/05/2023] [Accepted: 04/07/2023] [Indexed: 04/22/2023]
Abstract
Smoking tobacco cigarettes is a significant (cardiovascular) health risk factor. Although the number of tobacco cigarette users declined over the last decades, shisha smoking and e-cigarette vaping partially compensated for this health benefit. E-cigarettes may create highly addicted dual users (vaping and smoking). E-cigarettes seem not to represent a healthier alternative to tobacco smoking, although they may be less harmful. E-cigarette vaping causes oxidative stress, inflammation, endothelial dysfunction, and associated cardiovascular sequelae. This is primarily due to a significant overlap of toxic compounds in the vapor compared to tobacco smoke and, accordingly, a substantial overlap of pathomechanistic features between vaping and smoking. Whereas the main toxins in vapor are reactive aldehydes such as formaldehyde and acrolein, the toxic mixture in smoke is more complex, comprising particulate matter, reactive gases, transition metals, volatile organic compounds, and N-nitrosamines. However, it seems that both lifestyle drugs impair endothelial function to a quite similar extent, which may be due to the role of oxidative stress as the central pathomechanism to mediate endothelial dysfunction and vascular damage. Finally, the main selling argument for e-cigarette use that they help to quit smoking and get rid of nicotine addiction may be false because it seems that e-cigarettes instead trigger the opposite-younger entrance age and more frequent use. With our review, we summarize the adverse health impact of tobacco cigarettes and e-cigarettes, emphasizing the detrimental effects on endothelial function and cardiovascular health.
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Affiliation(s)
- Andreas Daiber
- Department of Cardiology 1, University Medical Center of the Johannes Gutenberg University, Langenbeckstr. 1, 55131, Mainz, Germany.
- German Center for Cardiovascular Research (DZHK), Partnersite Rhine-Main, Mainz, Germany.
| | - Marin Kuntic
- Department of Cardiology 1, University Medical Center of the Johannes Gutenberg University, Langenbeckstr. 1, 55131, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partnersite Rhine-Main, Mainz, Germany
| | - Matthias Oelze
- Department of Cardiology 1, University Medical Center of the Johannes Gutenberg University, Langenbeckstr. 1, 55131, Mainz, Germany
| | - Omar Hahad
- Department of Cardiology 1, University Medical Center of the Johannes Gutenberg University, Langenbeckstr. 1, 55131, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partnersite Rhine-Main, Mainz, Germany
| | - Thomas Münzel
- Department of Cardiology 1, University Medical Center of the Johannes Gutenberg University, Langenbeckstr. 1, 55131, Mainz, Germany.
- German Center for Cardiovascular Research (DZHK), Partnersite Rhine-Main, Mainz, Germany.
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Bayo Jimenez MT, Hahad O, Kuntic M, Daiber A, Münzel T. Noise, Air, and Heavy Metal Pollution as Risk Factors for Endothelial Dysfunction. Eur Cardiol 2023; 18:e09. [PMID: 37377448 PMCID: PMC10291605 DOI: 10.15420/ecr.2022.41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 12/12/2022] [Indexed: 06/29/2023] Open
Abstract
During the last two decades, large epidemiological studies have shown that the physical environment, including noise, air pollution or heavy metals, have a considerable impact on human health. It is known that the most common cardiovascular risk factors are all associated with endothelial dysfunction. Vascular tone, circulation of blood cells, inflammation, and platelet activity are some of the most essential functions regulated by the endothelium that suffer negative effects as a consequence of environmental pollution, causing endothelial dysfunction. In this review, we delineate the impact of environmental risk factors in connection to endothelial function. On a mechanistic level, a significant number of studies suggest the involvement of endothelial dysfunction to fundamentally drive the adverse endothelium health effects of the different pollutants. We focus on well-established studies that demonstrate the negative effects on the endothelium, with a focus on air, noise, and heavy metal pollution. This in-depth review on endothelial dysfunction as a consequence of the physical environment aims to contribute to the associated research needs by evaluating current findings from human and animal studies. From a public health perspective, these findings may also help to reinforce efforts promoting the research for adequate promising biomarkers for cardiovascular diseases since endothelial function is considered a hallmark of environmental stressor health effects.
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Affiliation(s)
- Maria Teresa Bayo Jimenez
- Department of Cardiology – Cardiology I, University Medical Center of the Johannes Gutenberg University MainzMainz, Germany
| | - Omar Hahad
- Department of Cardiology – Cardiology I, University Medical Center of the Johannes Gutenberg University MainzMainz, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Rhine-MainMainz, Germany
- Leibniz Institute for Resilience Research (LIR)Mainz, Germany
| | - Marin Kuntic
- Department of Cardiology – Cardiology I, University Medical Center of the Johannes Gutenberg University MainzMainz, Germany
| | - Andreas Daiber
- Department of Cardiology – Cardiology I, University Medical Center of the Johannes Gutenberg University MainzMainz, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Rhine-MainMainz, Germany
| | - Thomas Münzel
- Department of Cardiology – Cardiology I, University Medical Center of the Johannes Gutenberg University MainzMainz, Germany
- German Centre for Cardiovascular Research (DZHK), partner site Rhine-MainMainz, Germany
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12
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Hahad O, Kuntic M, Kuntic I, Daiber A, Münzel T. Tobacco smoking and vascular biology and function: evidence from human studies. Pflugers Arch 2023:10.1007/s00424-023-02805-z. [PMID: 36961561 DOI: 10.1007/s00424-023-02805-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 03/02/2023] [Accepted: 03/11/2023] [Indexed: 03/25/2023]
Abstract
Tobacco cigarette smoking is among the most complex and least understood health risk factors. A deeper insight into the pathophysiological actions of smoking exposure is of special importance as smoking is a major cause of chronic non-communicable diseases, in particular of cardiovascular disease as well as risk factors such as atherosclerosis and arterial hypertension. It is well known that smoking exerts its negative effects on cardiovascular health through various interdependent pathophysiological actions including hemodynamic and autonomic alterations, oxidative stress, inflammation, endothelial dysfunction, thrombosis, and hyperlipidemia. Importantly, impaired vascular endothelial function is acknowledged as an early key event in the initiation and progression of smoking-induced atherosclerosis. Increasing evidence from human studies indicates that cigarette smoke exposure associates with a pathological state of the vascular endothelium mainly characterized by reduced vascular nitric oxide bioavailability due to increased vascular superoxide production. In the present overview, we provide compact evidence on the effects of tobacco cigarette smoke exposure on vascular biology and function in humans centered on main drivers of adverse cardiovascular effects including endothelial dysfunction, inflammation, and oxidative stress.
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Affiliation(s)
- Omar Hahad
- Department of Cardiology - Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany.
- German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany.
| | - Marin Kuntic
- Department of Cardiology - Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Ivana Kuntic
- Department of Cardiology - Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
| | - Andreas Daiber
- Department of Cardiology - Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany
| | - Thomas Münzel
- Department of Cardiology - Cardiology I, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany
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13
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Münzel T, Daiber A. Vascular redox signaling, eNOS uncoupling and endothelial dysfunction in the setting of transportation noise exposure or chronic treatment with organic nitrates. Antioxid Redox Signal 2023; 38:1001-1021. [PMID: 36719770 PMCID: PMC10171967 DOI: 10.1089/ars.2023.0006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
SIGNIFICANCE Cardiovascular disease and drug-induced health side effects are frequently associated with - or even caused by - an imbalance between the concentrations of reactive oxygen and nitrogen species (RONS) and antioxidants respectively determining the metabolism of these harmful oxidants. RECENT ADVANCES According to the "kindling radical" hypothesis, initial formation of RONS may further trigger the additional activation of RONS formation under certain pathological conditions. The present review will specifically focus on a dysfunctional, uncoupled endothelial nitric oxide synthase (eNOS) caused by RONS in the setting of transportation noise exposure or chronic treatment with organic nitrates, especially nitroglycerin. We will further describe the various "redox switches" that are proposed to be involved in the uncoupling process of eNOS. CRITICAL ISSUES In particular, the oxidative depletion of tetrahydrobiopterin (BH4), and S-glutathionylation of the eNOS reductase domain will be highlighted as major pathways for eNOS uncoupling upon noise exposure or nitroglycerin treatment. In addition, oxidative disruption of the eNOS dimer, inhibitory phosphorylation of eNOS at threonine or tyrosine residues, redox-triggered accumulation of asymmetric dimethylarginine (ADMA) and L-arginine deficiency will be discussed as alternative mechanisms of eNOS uncoupling. FUTURE DIRECTIONS The clinical consequences of eNOS dysfunction due to uncoupling on cardiovascular disease will be summarized also providing a template for future clinical studies on endothelial dysfunction caused by pharmacological or environmental risk factors.
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Affiliation(s)
- Thomas Münzel
- University Medical Center of the Johannes Gutenberg University Mainz, 39068, Cardiology I, Mainz, Rheinland-Pfalz, Germany;
| | - Andreas Daiber
- University Medical Center of the Johannes Gutenberg University Mainz, 39068, Cardiology I, Mainz, Rheinland-Pfalz, Germany;
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Muacevic A, Adler JR. The Role of Vitamin C in Human Immunity and Its Treatment Potential Against COVID-19: A Review Article. Cureus 2023; 15:e33740. [PMID: 36793827 PMCID: PMC9925039 DOI: 10.7759/cureus.33740] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 01/12/2023] [Indexed: 01/15/2023] Open
Abstract
The outbreak of the COVID-19 pandemic has left clinicians around the world searching for viable prevention and treatment options to use against the virus. The important physiologic properties of vitamin C have been well documented regarding its use by immune cells and its role as an antioxidant. It has previously shown potential as a prophylactic and treatment option for other respiratory viruses, and because of this, there has been intrigue into whether these positive outcomes translate into a cost-effective prevention and treatment option for COVID-19. To this point, there have only been a few clinical trials performed to assess the validity of this notion, with very few showing definitive positive outcomes when vitamin C has been incorporated into prophylactic or treatment protocols to use against coronavirus. When being used to specifically treat the severe complications that arise from COVID-19, vitamin C is a reliable option to treat COVID-19-induced sepsis but not pneumonia or acute respiratory distress syndrome (ARDS). As a treatment option, high-dose therapy has shown flashes of promise in a few studies although investigators in these studies often subject the testing group to multimodal therapies that include vitamin C as opposed to just vitamin C alone. Given the role that vitamin C has shown to uphold regarding the human immune response, it is currently advised for all individuals to maintain a normal physiologic range of plasma vitamin C through diet or supplements for adequate prophylactic protection against the virus. More research with definitive outcomes will be needed before it is recommended to provide high-dose vitamin C therapy to prevent or treat COVID-19.
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15
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Hahad O, Beutel M, Gilan DA, Michal M, Schulz A, Pfeiffer N, König J, Lackner K, Wild P, Daiber A, Münzel T. The association of smoking and smoking cessation with prevalent and incident symptoms of depression, anxiety, and sleep disturbance in the general population. J Affect Disord 2022; 313:100-109. [PMID: 35777492 DOI: 10.1016/j.jad.2022.06.083] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2022] [Revised: 06/01/2022] [Accepted: 06/23/2022] [Indexed: 11/18/2022]
Abstract
BACKGROUND Smoking is a well-established risk factor for chronic non-communicable diseases. However, the relationship between cigarette smoking and the risk of developing mental health conditions remains largely elusive. This study examined the relationship between cigarette smoking as well as smoking cessation and prevalent and incident symptoms of depression, anxiety, and sleep disturbance in the general population. METHODS In a cohort of 15,010 individuals from the Gutenberg Health Study (aged 35-74 years at enrollment), prevalent (at baseline from 2007 to 2012) and incident symptoms (at follow-up from 2012 to 2017) of depression, anxiety, and sleep disturbance were determined by validated questionnaires and/or medical records. Smoking status, pack-years of smoking in current and former smokers, and years since quitting smoking in former smokers were assessed by a standardized computer-assisted interview. RESULTS In multivariable logistic regression models with comprehensive adjustment for covariates, smoking status was independently associated with prevalent and incident symptoms of depression (Patient Health Questionnaire-9 ≥ 10), whereas this association was weaker for anxiety (Generalized Anxiety Disorder Scale-2 ≥ 3) and sleep disturbance (Patient Health Questionnaire-9 > 1). Among current and former smokers, smoking ≥30 or ≥10 pack-years, respectively, yielded in general the highest effect estimates. Smoking cessation was weakly associated with the prevalence and incidence of all outcomes, here consistent associations were observed for prevalent symptoms of depression. LIMITATIONS The observational nature of the study does not allow for causal inferences. CONCLUSIONS The results of the present study suggest that cigarette smoking is positively and that smoking cessation is negatively associated with symptoms of common mental health conditions, in particular of depression.
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Affiliation(s)
- Omar Hahad
- Department of Cardiology - Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany; Leibniz Institute for Resilience Research (LIR), Mainz, Germany.
| | - Manfred Beutel
- Department of Psychosomatic Medicine and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Donya A Gilan
- Leibniz Institute for Resilience Research (LIR), Mainz, Germany; Department of Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Matthias Michal
- German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany; Department of Psychosomatic Medicine and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Andreas Schulz
- Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Norbert Pfeiffer
- Department of Ophthalmology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Jochem König
- Institute of Medical Biostatistics, Epidemiology & Informatics, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Karl Lackner
- Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Philipp Wild
- Department of Cardiology - Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany; Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Andreas Daiber
- Department of Cardiology - Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Thomas Münzel
- Department of Cardiology - Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany; German Center for Cardiovascular Research (DZHK), partner site Rhine-Main, Mainz, Germany; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
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16
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Zhang H, Kim H, Park BW, Noh M, Kim Y, Park J, Park JH, Kim JJ, Sim WS, Ban K, Park HJ, Kwon YG. CU06-1004 enhances vascular integrity and improves cardiac remodeling by suppressing edema and inflammation in myocardial ischemia-reperfusion injury. Exp Mol Med 2022; 54:23-34. [PMID: 34997212 PMCID: PMC8814060 DOI: 10.1038/s12276-021-00720-w] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 11/11/2021] [Accepted: 11/15/2021] [Indexed: 11/13/2022] Open
Abstract
Ischemia-reperfusion (I/R) injury accelerates the cardiomyocytes (CMs) death by oxidative stress, and thereby deteriorates cardiac function. There has been a paradigm shift in the therapeutic perspective more towards the prevention or amelioration of damage caused by reperfusion. Cardiac microvascular endothelial cells (CMECs) are more vulnerable to reperfusion injury and play the crucial roles more than CMs in the pathological process of early I/R injury. In this study, we investigate that CU06-1004, as a vascular leakage blocker, can improve cardiac function by inhibiting CMEC's hyperpermeability and subsequently reducing the neutrophil's plugging and infiltration in infarcted hearts. CU06-1004 was delivered intravenously 5 min before reperfusion and the rats were randomly divided into three groups: (1) vehicle, (2) low-CU06-1004 (1 mg/kg, twice at 24 h intervals), and (3) high-CU06-1004 (5 mg/kg, once before reperfusion). CU06-1004 treatment reduced necrotic size and cardiac edema by enhancing vascular integrity, as demonstrated by the presence of intact junction proteins on CMECs and surrounding pericytes in early I/R injury. It also decreased the expression of vascular cell adhesion molecule 1 (VCAM-1) on CMECs, resulting in reduced infiltration of neutrophils and macrophages. Echocardiography showed that the CU06-1004 treatment significantly improved cardiac function compared with the vehicle group. Interestingly, single high-dose treatment with CU06-1004 provided a greater functional improvement than repetitive low-dose treatment until 8 weeks post I/R. These findings demonstrate that CU06-1004 enhances vascular integrity and improves cardiac function by preventing lethal myocardial I/R injury. It can provide a promising therapeutic option, as potential adjunctive therapy to current reperfusion strategies.
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Affiliation(s)
- Haiying Zhang
- grid.15444.300000 0004 0470 5454Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-749 Republic of Korea ,R&D Department, Curacle Co. Ltd, Seongnam-si, Republic of Korea
| | - Hyeok Kim
- grid.411947.e0000 0004 0470 4224Department of Medical Life Science, College of Medicine, The Catholic University of Korea, Seoul, 06591 Republic of Korea
| | - Bong Woo Park
- grid.411947.e0000 0004 0470 4224Department of Medical Life Science, College of Medicine, The Catholic University of Korea, Seoul, 06591 Republic of Korea
| | - Minyoung Noh
- grid.15444.300000 0004 0470 5454Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-749 Republic of Korea
| | - Yeomyeong Kim
- grid.15444.300000 0004 0470 5454Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-749 Republic of Korea
| | - Jeongeun Park
- grid.15444.300000 0004 0470 5454Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-749 Republic of Korea
| | - Jae-Hyun Park
- grid.411947.e0000 0004 0470 4224Department of Medical Life Science, College of Medicine, The Catholic University of Korea, Seoul, 06591 Republic of Korea
| | - Jin-Ju Kim
- grid.411947.e0000 0004 0470 4224Department of Medical Life Science, College of Medicine, The Catholic University of Korea, Seoul, 06591 Republic of Korea
| | - Woo-Sup Sim
- grid.411947.e0000 0004 0470 4224Department of Medical Life Science, College of Medicine, The Catholic University of Korea, Seoul, 06591 Republic of Korea
| | - Kiwon Ban
- grid.35030.350000 0004 1792 6846Department of Biomedical Sciences, City University of Hong Kong, Kowloon Tong, 999077 Hong Kong
| | - Hun-Jun Park
- Department of Medical Life Science, College of Medicine, The Catholic University of Korea, Seoul, 06591, Republic of Korea. .,Division of Cardiology, Department of Internal Medicine, The Catholic University of Korea, Banpo-daero 222, Seocho-gu, Seoul, 137701, Republic of Korea.
| | - Young-Guen Kwon
- Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, 120-749, Republic of Korea.
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17
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Kuntic M, Hahad O, Münzel T, Daiber A. Lebensstil und kardiovaskuläre Gesundheit – wie schädlich sind E-Zigaretten und Shisha-Rauchen? AKTUELLE KARDIOLOGIE 2021. [DOI: 10.1055/a-1545-3107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
ZusammenfassungTabakrauchen ist ein Hauptauslöser chronischer nicht übertragbarer Krankheiten und ein Risikofaktor für kardiovaskuläre und pulmonale Erkrankungen. Obwohl der weltweite Tabakkonsum während der letzten 2 Jahrzehnte reduziert wurde, zeigt der Gebrauch von E-Zigaretten und Wasserpfeifen (Shisha) eine pandemische Zunahme mit hohem Anteil jüngerer Anwender. E-Zigaretten sind keine komplett schadensfreie Alternative zu herkömmlichen Tabakzigaretten, auch weil die zahlreichen Geschmacksaromen und die einfache/schnelle Verwendung eine steigende Zahl von abhängigen Anwendern hervorbringt. E-Zigaretten sind nicht unbedingt geeignet, die Nikotinabhängigkeit hinter sich zu lassen. Diese Arbeit bietet eine Übersicht über die kardiovaskulären Gesundheitsauswirkungen des Shisharauchens und E-Zigaretten-Dampfens mit Fokus auf die negativen Effekte auf die Endothelfunktion. Die schädlichen biologischen Auswirkungen der toxischen Inhaltsstoffe dieser Produkte werden vor allem im Hinblick auf
oxidativen Stress und Entzündungsreaktionen diskutiert. Abschließend wird der aktuelle Stand hinsichtlich der Empfehlungen, gesetzlichen Regelungen und kommerziellen Werbung kurz zusammengefasst.
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Affiliation(s)
- Marin Kuntic
- Zentrum für Kardiologie, Kardiologie I, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz, Deutschland
| | - Omar Hahad
- Zentrum für Kardiologie, Kardiologie I, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz, Deutschland
- Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Standort Rhein-Main, Mainz, Deutschland
| | - Thomas Münzel
- Zentrum für Kardiologie, Kardiologie I, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz, Deutschland
- Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Standort Rhein-Main, Mainz, Deutschland
| | - Andreas Daiber
- Zentrum für Kardiologie, Kardiologie I, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz, Deutschland
- Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Standort Rhein-Main, Mainz, Deutschland
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18
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Stone RM, Ainslie PN, Tremblay JC, Akins JD, MacLeod DB, Tymko MM, DeSouza CA, Bain AR. GLOBAL REACH 2018: intra-arterial vitamin C improves endothelial-dependent vasodilatory function in humans at high altitude. J Physiol 2021; 600:1373-1383. [PMID: 34743333 DOI: 10.1113/jp282281] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/11/2021] [Indexed: 12/20/2022] Open
Abstract
High altitude-induced hypoxaemia is often associated with peripheral vascular dysfunction. However, the basic mechanism(s) underlying high-altitude vascular impairments remains unclear. This study tested the hypothesis that oxidative stress contributes to the impairments in endothelial function during early acclimatization to high altitude. Ten young healthy lowlanders were tested at sea level (344 m) and following 4-6 days at high altitude (4300 m). Vascular endothelial function was determined using the isolated perfused forearm technique with forearm blood flow (FBF) measured by strain-gauge venous occlusion plethysmography. FBF was quantified in response to acetylcholine (ACh), sodium nitroprusside (SNP) and a co-infusion of ACh with the antioxidant vitamin C (ACh+VitC). The total FBF response to ACh (area under the curve) was ∼30% lower at high altitude than at sea level (P = 0.048). There was no difference in the response to SNP at high altitude (P = 0.860). At sea level, the co-infusion of ACh+VitC had no influence on the FBF dose response (P = 0.268); however, at high altitude ACh+VitC resulted in an average increase in the FBF dose response by ∼20% (P = 0.019). At high altitude, the decreased FBF response to ACh, and the increase in FBF in response to ACh+VitC, were associated with the magnitude of arterial hypoxaemia (R2 = 0.60, P = 0.008 and R2 = 0.63, P = 0.006, respectively). Collectively, these data support the hypothesis that impairments in vascular endothelial function at high altitude are in part attributable to oxidative stress, a consequence of the magnitude of hypoxaemia. These data extend our basic understanding of vascular (mal)adaptation to high-altitude sojourns, with important implications for understanding the aetiology of high altitude-related vascular dysfunction. KEY POINTS: Vascular dysfunction has been demonstrated in lowlanders at high altitude (>4000 m). However, the extent of impairment and the delineation of contributing mechanisms have remained unclear. Using the gold-standard isolated perfused forearm model, we determined the extent of vasodilatory dysfunction and oxidative stress as a contributing mechanism in healthy lowlanders before and 4-6 days after rapid ascent to 4300 m. The total forearm blood flow response to acetylcholine at high altitude was decreased by ∼30%. Co-infusion of acetylcholine with the antioxidant vitamin C partially restored the total forearm blood flow by ∼20%. The magnitude of forearm blood flow reduction, as well as the impact of oxidative stress, was positively associated with the individual severity of hypoxaemia. These data extend our basic understanding of vascular (mal)adaptation to high-altitude sojourns, with important implications for understanding the aetiology of high altitude-related changes in endothelial-mediated vasodilatory function.
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Affiliation(s)
- Rachel M Stone
- Faculty of Human Kinetics, University of Windsor, Ontario, Canada
| | - Philip N Ainslie
- Kelowna, Centre for Heart Lung and Vascular Health, University of British Columbia, Vancouver, Canada
| | - Joshua C Tremblay
- Kelowna, Centre for Heart Lung and Vascular Health, University of British Columbia, Vancouver, Canada
| | | | - David B MacLeod
- Duke University School of Medicine, Durham, North Carolina, USA
| | | | | | - Anthony R Bain
- Faculty of Human Kinetics, University of Windsor, Ontario, Canada
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19
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Olabiyi AA, AlliSmith YR, Ukwenya VO. Quercetin enhances sexual behavior and improves ectonucleotidases activity in the hypothalamus of rats treated with cyclosporine. J Food Biochem 2021; 45:e13864. [PMID: 34263471 DOI: 10.1111/jfbc.13864] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 05/04/2021] [Accepted: 06/30/2021] [Indexed: 01/04/2023]
Abstract
In order to confirm the erectile potential of Quercetin (Q) in cyclosporine-induced hypertensive rats, this research assesses the influence of Q on the ectonucleotidases and adenosine deaminase (ADA) in the brains of rats. Male Wistar rats (200 g-250 g) were divided into five groups at random: Normal control (CTRL), cyclosporine-induced hypertensive rats (25 mg kg day-1 ) (HT) group, positive control (Sildenafil [SIL], 5 mg kg day-1 ), Quercetin 25 mg kg day-1 (25 Q), and Quercetin 50 mg kg day-1 (50 Q). Aside from standard diet-fed male rats; cyclosporine was given i.p for the period of 30 days as well as Q orally while the female rats were only given a standard diet. The animals were subjected to sexual activity (copulation) after which the male rat hypothalamus was dissected for biochemical examination (E-NTPDase activities, ecto-5'-nucleotidase as well as ADA and also levels of nitric oxide [NO]). We observed that Q enhanced copulatory behavior as evident in mounting, intromission, ejaculation numbers, and latencies. A substantial (p < .05) increase in the activity of E-NTPDase (ATP and ADP as substrate) without any notable difference in the action of ecto-5' nucleotidase was facilitated by cyclosporine-induction when compared to the CTRL. The 50 mg/kg, however, had the highest reversal effect in accordance with dose manner. Also, cyclosporine increased ADA activity with a concomitant reduction of NO level while both doses of Q down-regulated ADA activity and, increased NO levels. Enhanced sexual behavior, modulation of ectonucleotidases as well as ADA activity and increased NO levels suggest that Q-rich plant foods may be promising sources of dietary phytonutrients for erectile dysfunction (ED) management. PRACTICAL APPLICATIONS: Behavioral and biochemical assays evaluated showed that Q significantly enhanced sexual behavior as well as improved ATP bioavailability in cyclosporine-induced erectile dysfunctional rats. The modulatory effects of Q on ectonucleotidases, along with its ability to minimize adenosine deaminase activity and increase nitric oxide levels, indicate that Q-rich plants and/or plant foods may be promising sources of dietary phytonutrients for erectile dysfunction management.
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Affiliation(s)
- Ayodeji Augustine Olabiyi
- Functional Food and Nutraceutical Unit, Medical Biochemistry Department, Afe Babalola University, Ado Ekiti, Nigeria
| | | | - Victor Okoliko Ukwenya
- Department of Human Anatomy, School of Health and Health Technology, Federal University of Technology, Akure, Nigeria
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20
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Xu S, Ilyas I, Little PJ, Li H, Kamato D, Zheng X, Luo S, Li Z, Liu P, Han J, Harding IC, Ebong EE, Cameron SJ, Stewart AG, Weng J. Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies. Pharmacol Rev 2021; 73:924-967. [PMID: 34088867 DOI: 10.1124/pharmrev.120.000096] [Citation(s) in RCA: 553] [Impact Index Per Article: 138.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The endothelium, a cellular monolayer lining the blood vessel wall, plays a critical role in maintaining multiorgan health and homeostasis. Endothelial functions in health include dynamic maintenance of vascular tone, angiogenesis, hemostasis, and the provision of an antioxidant, anti-inflammatory, and antithrombotic interface. Dysfunction of the vascular endothelium presents with impaired endothelium-dependent vasodilation, heightened oxidative stress, chronic inflammation, leukocyte adhesion and hyperpermeability, and endothelial cell senescence. Recent studies have implicated altered endothelial cell metabolism and endothelial-to-mesenchymal transition as new features of endothelial dysfunction. Endothelial dysfunction is regarded as a hallmark of many diverse human panvascular diseases, including atherosclerosis, hypertension, and diabetes. Endothelial dysfunction has also been implicated in severe coronavirus disease 2019. Many clinically used pharmacotherapies, ranging from traditional lipid-lowering drugs, antihypertensive drugs, and antidiabetic drugs to proprotein convertase subtilisin/kexin type 9 inhibitors and interleukin 1β monoclonal antibodies, counter endothelial dysfunction as part of their clinical benefits. The regulation of endothelial dysfunction by noncoding RNAs has provided novel insights into these newly described regulators of endothelial dysfunction, thus yielding potential new therapeutic approaches. Altogether, a better understanding of the versatile (dys)functions of endothelial cells will not only deepen our comprehension of human diseases but also accelerate effective therapeutic drug discovery. In this review, we provide a timely overview of the multiple layers of endothelial function, describe the consequences and mechanisms of endothelial dysfunction, and identify pathways to effective targeted therapies. SIGNIFICANCE STATEMENT: The endothelium was initially considered to be a semipermeable biomechanical barrier and gatekeeper of vascular health. In recent decades, a deepened understanding of the biological functions of the endothelium has led to its recognition as a ubiquitous tissue regulating vascular tone, cell behavior, innate immunity, cell-cell interactions, and cell metabolism in the vessel wall. Endothelial dysfunction is the hallmark of cardiovascular, metabolic, and emerging infectious diseases. Pharmacotherapies targeting endothelial dysfunction have potential for treatment of cardiovascular and many other diseases.
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Affiliation(s)
- Suowen Xu
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (S.X., I.I., X.Z., S.L., J.W.); Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, Australia (P.J.L.); School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia (P.J.L., D.K.); Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China (Z.L., P.L.); College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H.); Department of Bioengineering, Northeastern University, Boston, Massachusetts (I.C.H., E.E.E.); Department of Chemical Engineering, Northeastern University, Boston, Massachusetts (E.E.E.); Department of Neuroscience, Albert Einstein College of Medicine, New York, New York (E.E.E.); Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (S.J.C.); and ARC Centre for Personalised Therapeutics Technologies, Department of Biochemistry and Pharmacology, School of Biomedical Science, University of Melbourne, Parkville, Victoria, Australia (A.G.S.)
| | - Iqra Ilyas
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (S.X., I.I., X.Z., S.L., J.W.); Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, Australia (P.J.L.); School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia (P.J.L., D.K.); Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China (Z.L., P.L.); College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H.); Department of Bioengineering, Northeastern University, Boston, Massachusetts (I.C.H., E.E.E.); Department of Chemical Engineering, Northeastern University, Boston, Massachusetts (E.E.E.); Department of Neuroscience, Albert Einstein College of Medicine, New York, New York (E.E.E.); Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (S.J.C.); and ARC Centre for Personalised Therapeutics Technologies, Department of Biochemistry and Pharmacology, School of Biomedical Science, University of Melbourne, Parkville, Victoria, Australia (A.G.S.)
| | - Peter J Little
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (S.X., I.I., X.Z., S.L., J.W.); Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, Australia (P.J.L.); School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia (P.J.L., D.K.); Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China (Z.L., P.L.); College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H.); Department of Bioengineering, Northeastern University, Boston, Massachusetts (I.C.H., E.E.E.); Department of Chemical Engineering, Northeastern University, Boston, Massachusetts (E.E.E.); Department of Neuroscience, Albert Einstein College of Medicine, New York, New York (E.E.E.); Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (S.J.C.); and ARC Centre for Personalised Therapeutics Technologies, Department of Biochemistry and Pharmacology, School of Biomedical Science, University of Melbourne, Parkville, Victoria, Australia (A.G.S.)
| | - Hong Li
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (S.X., I.I., X.Z., S.L., J.W.); Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, Australia (P.J.L.); School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia (P.J.L., D.K.); Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China (Z.L., P.L.); College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H.); Department of Bioengineering, Northeastern University, Boston, Massachusetts (I.C.H., E.E.E.); Department of Chemical Engineering, Northeastern University, Boston, Massachusetts (E.E.E.); Department of Neuroscience, Albert Einstein College of Medicine, New York, New York (E.E.E.); Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (S.J.C.); and ARC Centre for Personalised Therapeutics Technologies, Department of Biochemistry and Pharmacology, School of Biomedical Science, University of Melbourne, Parkville, Victoria, Australia (A.G.S.)
| | - Danielle Kamato
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (S.X., I.I., X.Z., S.L., J.W.); Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, Australia (P.J.L.); School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia (P.J.L., D.K.); Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China (Z.L., P.L.); College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H.); Department of Bioengineering, Northeastern University, Boston, Massachusetts (I.C.H., E.E.E.); Department of Chemical Engineering, Northeastern University, Boston, Massachusetts (E.E.E.); Department of Neuroscience, Albert Einstein College of Medicine, New York, New York (E.E.E.); Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (S.J.C.); and ARC Centre for Personalised Therapeutics Technologies, Department of Biochemistry and Pharmacology, School of Biomedical Science, University of Melbourne, Parkville, Victoria, Australia (A.G.S.)
| | - Xueying Zheng
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (S.X., I.I., X.Z., S.L., J.W.); Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, Australia (P.J.L.); School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia (P.J.L., D.K.); Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China (Z.L., P.L.); College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H.); Department of Bioengineering, Northeastern University, Boston, Massachusetts (I.C.H., E.E.E.); Department of Chemical Engineering, Northeastern University, Boston, Massachusetts (E.E.E.); Department of Neuroscience, Albert Einstein College of Medicine, New York, New York (E.E.E.); Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (S.J.C.); and ARC Centre for Personalised Therapeutics Technologies, Department of Biochemistry and Pharmacology, School of Biomedical Science, University of Melbourne, Parkville, Victoria, Australia (A.G.S.)
| | - Sihui Luo
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (S.X., I.I., X.Z., S.L., J.W.); Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, Australia (P.J.L.); School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia (P.J.L., D.K.); Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China (Z.L., P.L.); College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H.); Department of Bioengineering, Northeastern University, Boston, Massachusetts (I.C.H., E.E.E.); Department of Chemical Engineering, Northeastern University, Boston, Massachusetts (E.E.E.); Department of Neuroscience, Albert Einstein College of Medicine, New York, New York (E.E.E.); Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (S.J.C.); and ARC Centre for Personalised Therapeutics Technologies, Department of Biochemistry and Pharmacology, School of Biomedical Science, University of Melbourne, Parkville, Victoria, Australia (A.G.S.)
| | - Zhuoming Li
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (S.X., I.I., X.Z., S.L., J.W.); Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, Australia (P.J.L.); School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia (P.J.L., D.K.); Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China (Z.L., P.L.); College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H.); Department of Bioengineering, Northeastern University, Boston, Massachusetts (I.C.H., E.E.E.); Department of Chemical Engineering, Northeastern University, Boston, Massachusetts (E.E.E.); Department of Neuroscience, Albert Einstein College of Medicine, New York, New York (E.E.E.); Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (S.J.C.); and ARC Centre for Personalised Therapeutics Technologies, Department of Biochemistry and Pharmacology, School of Biomedical Science, University of Melbourne, Parkville, Victoria, Australia (A.G.S.)
| | - Peiqing Liu
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (S.X., I.I., X.Z., S.L., J.W.); Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, Australia (P.J.L.); School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia (P.J.L., D.K.); Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China (Z.L., P.L.); College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H.); Department of Bioengineering, Northeastern University, Boston, Massachusetts (I.C.H., E.E.E.); Department of Chemical Engineering, Northeastern University, Boston, Massachusetts (E.E.E.); Department of Neuroscience, Albert Einstein College of Medicine, New York, New York (E.E.E.); Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (S.J.C.); and ARC Centre for Personalised Therapeutics Technologies, Department of Biochemistry and Pharmacology, School of Biomedical Science, University of Melbourne, Parkville, Victoria, Australia (A.G.S.)
| | - Jihong Han
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (S.X., I.I., X.Z., S.L., J.W.); Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, Australia (P.J.L.); School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia (P.J.L., D.K.); Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China (Z.L., P.L.); College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H.); Department of Bioengineering, Northeastern University, Boston, Massachusetts (I.C.H., E.E.E.); Department of Chemical Engineering, Northeastern University, Boston, Massachusetts (E.E.E.); Department of Neuroscience, Albert Einstein College of Medicine, New York, New York (E.E.E.); Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (S.J.C.); and ARC Centre for Personalised Therapeutics Technologies, Department of Biochemistry and Pharmacology, School of Biomedical Science, University of Melbourne, Parkville, Victoria, Australia (A.G.S.)
| | - Ian C Harding
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (S.X., I.I., X.Z., S.L., J.W.); Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, Australia (P.J.L.); School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia (P.J.L., D.K.); Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China (Z.L., P.L.); College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H.); Department of Bioengineering, Northeastern University, Boston, Massachusetts (I.C.H., E.E.E.); Department of Chemical Engineering, Northeastern University, Boston, Massachusetts (E.E.E.); Department of Neuroscience, Albert Einstein College of Medicine, New York, New York (E.E.E.); Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (S.J.C.); and ARC Centre for Personalised Therapeutics Technologies, Department of Biochemistry and Pharmacology, School of Biomedical Science, University of Melbourne, Parkville, Victoria, Australia (A.G.S.)
| | - Eno E Ebong
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (S.X., I.I., X.Z., S.L., J.W.); Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, Australia (P.J.L.); School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia (P.J.L., D.K.); Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China (Z.L., P.L.); College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H.); Department of Bioengineering, Northeastern University, Boston, Massachusetts (I.C.H., E.E.E.); Department of Chemical Engineering, Northeastern University, Boston, Massachusetts (E.E.E.); Department of Neuroscience, Albert Einstein College of Medicine, New York, New York (E.E.E.); Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (S.J.C.); and ARC Centre for Personalised Therapeutics Technologies, Department of Biochemistry and Pharmacology, School of Biomedical Science, University of Melbourne, Parkville, Victoria, Australia (A.G.S.)
| | - Scott J Cameron
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (S.X., I.I., X.Z., S.L., J.W.); Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, Australia (P.J.L.); School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia (P.J.L., D.K.); Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China (Z.L., P.L.); College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H.); Department of Bioengineering, Northeastern University, Boston, Massachusetts (I.C.H., E.E.E.); Department of Chemical Engineering, Northeastern University, Boston, Massachusetts (E.E.E.); Department of Neuroscience, Albert Einstein College of Medicine, New York, New York (E.E.E.); Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (S.J.C.); and ARC Centre for Personalised Therapeutics Technologies, Department of Biochemistry and Pharmacology, School of Biomedical Science, University of Melbourne, Parkville, Victoria, Australia (A.G.S.)
| | - Alastair G Stewart
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (S.X., I.I., X.Z., S.L., J.W.); Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, Australia (P.J.L.); School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia (P.J.L., D.K.); Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China (Z.L., P.L.); College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H.); Department of Bioengineering, Northeastern University, Boston, Massachusetts (I.C.H., E.E.E.); Department of Chemical Engineering, Northeastern University, Boston, Massachusetts (E.E.E.); Department of Neuroscience, Albert Einstein College of Medicine, New York, New York (E.E.E.); Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (S.J.C.); and ARC Centre for Personalised Therapeutics Technologies, Department of Biochemistry and Pharmacology, School of Biomedical Science, University of Melbourne, Parkville, Victoria, Australia (A.G.S.)
| | - Jianping Weng
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China (S.X., I.I., X.Z., S.L., J.W.); Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, Australia (P.J.L.); School of Pharmacy, Pharmacy Australia Centre of Excellence, The University of Queensland, Woolloongabba, Queensland, Australia (P.J.L., D.K.); Department of Medical Biotechnology, School of Basic Medical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); The Research Center of Basic Integrative Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China (H.L.); Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, National and Local United Engineering Laboratory of Druggability and New Drugs Evaluation, Guangzhou, China (Z.L., P.L.); College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin, China (J.H.); Department of Bioengineering, Northeastern University, Boston, Massachusetts (I.C.H., E.E.E.); Department of Chemical Engineering, Northeastern University, Boston, Massachusetts (E.E.E.); Department of Neuroscience, Albert Einstein College of Medicine, New York, New York (E.E.E.); Department of Cardiovascular and Metabolic Sciences, Cleveland Clinic Lerner College of Medicine, Cleveland, Ohio (S.J.C.); and ARC Centre for Personalised Therapeutics Technologies, Department of Biochemistry and Pharmacology, School of Biomedical Science, University of Melbourne, Parkville, Victoria, Australia (A.G.S.)
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21
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Hahad O, Arnold N, Prochaska JH, Panova-Noeva M, Schulz A, Lackner KJ, Pfeiffer N, Schmidtmann I, Michal M, Beutel M, Wild PS, Keaney JF, Daiber A, Münzel T. Cigarette Smoking Is Related to Endothelial Dysfunction of Resistance, but Not Conduit Arteries in the General Population-Results From the Gutenberg Health Study. Front Cardiovasc Med 2021; 8:674622. [PMID: 34095261 PMCID: PMC8169997 DOI: 10.3389/fcvm.2021.674622] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 04/12/2021] [Indexed: 11/18/2022] Open
Abstract
Aims: Cigarette smoking is one of the most complex and least understood cardiovascular risk factors. Importantly, differences in the tobacco-related pathophysiology of endothelial dysfunction, an early event in atherogenesis, between circulatory beds remain elusive. Therefore, this study evaluated how smoking impacts endothelial function of conduit and resistance arteries in a large population-based cohort. Methods and results: 15,010 participants (aged 35–74 years) of the Gutenberg Health Study were examined at baseline from 2007 to 2012. Smoking status, pack-years of smoking, and years since quitting smoking were assessed by a computer-assisted interview. Endothelial function of conduit and resistance arteries was determined by flow-mediated dilation (FMD) of the brachial artery, reactive hyperemia index (RHI) using peripheral arterial tonometry, as well as by reflection index (RI) derived from digital photoplethysmography, respectively. Among all subjects, 45.8% had never smoked, 34.7% were former smokers, and 19.4% were current smokers. Mean cumulative smoking exposure was 22.1 ± 18.1 pack-years in current smokers and mean years since quitting was 18.9 ± 12.7 in former smokers. In multivariable linear regression models adjusted for typical confounders, smoking status, pack-years of smoking, and years since quitting smoking were independently associated with RHI and RI, while no association was found for FMD. Overall, no clear dose-dependent associations were observed between variables, whereby higher exposure tended to be associated with pronounced resistance artery endothelial dysfunction. Conclusions: Cigarette smoking is associated with altered endothelial function of resistance, but not conduit arteries. The present results suggest that smoking-induced endothelial dysfunction in different circulatory beds may exhibit a differential picture.
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Affiliation(s)
- Omar Hahad
- Department of Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
| | - Natalie Arnold
- Department of Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany
| | - Jürgen H Prochaska
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany.,Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.,Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Marina Panova-Noeva
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany.,Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.,Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Andreas Schulz
- Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Karl J Lackner
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany.,Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Norbert Pfeiffer
- Department of Ophthalmology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Irene Schmidtmann
- Institute of Medical Biostatistics, Epidemiology & Informatics, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Matthias Michal
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany.,Department of Psychosomatic Medicine and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Manfred Beutel
- Department of Psychosomatic Medicine and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Philipp S Wild
- German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany.,Preventive Cardiology and Preventive Medicine, Department of Cardiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.,Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - John F Keaney
- Division of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, MA, United States
| | - Andreas Daiber
- Department of Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany.,Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Thomas Münzel
- Department of Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany.,Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany
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22
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Kuntic M, Oelze M, Steven S, Kröller-Schön S, Stamm P, Kalinovic S, Frenis K, Vujacic-Mirski K, Bayo Jimenez MT, Kvandova M, Filippou K, Al Zuabi A, Brückl V, Hahad O, Daub S, Varveri F, Gori T, Huesmann R, Hoffmann T, Schmidt FP, Keaney JF, Daiber A, Münzel T. Short-term e-cigarette vapour exposure causes vascular oxidative stress and dysfunction: evidence for a close connection to brain damage and a key role of the phagocytic NADPH oxidase (NOX-2). Eur Heart J 2021; 41:2472-2483. [PMID: 31715629 PMCID: PMC7340357 DOI: 10.1093/eurheartj/ehz772] [Citation(s) in RCA: 141] [Impact Index Per Article: 35.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2019] [Revised: 09/12/2019] [Accepted: 10/19/2019] [Indexed: 12/19/2022] Open
Abstract
AIMS Electronic (e)-cigarettes have been marketed as a 'healthy' alternative to traditional combustible cigarettes and as an effective method of smoking cessation. There are, however, a paucity of data to support these claims. In fact, e-cigarettes are implicated in endothelial dysfunction and oxidative stress in the vasculature and the lungs. The mechanisms underlying these side effects remain unclear. Here, we investigated the effects of e-cigarette vapour on vascular function in smokers and experimental animals to determine the underlying mechanisms. METHODS AND RESULTS Acute e-cigarette smoking produced a marked impairment of endothelial function in chronic smokers determined by flow-mediated dilation. In mice, e-cigarette vapour without nicotine had more detrimental effects on endothelial function, markers of oxidative stress, inflammation, and lipid peroxidation than vapour containing nicotine. These effects of e-cigarette vapour were largely absent in mice lacking phagocytic NADPH oxidase (NOX-2) or upon treatment with the endothelin receptor blocker macitentan or the FOXO3 activator bepridil. We also established that the e-cigarette product acrolein, a reactive aldehyde, recapitulated many of the NOX-2-dependent effects of e-cigarette vapour using in vitro blood vessel incubation. CONCLUSIONS E-cigarette vapour exposure increases vascular, cerebral, and pulmonary oxidative stress via a NOX-2-dependent mechanism. Our study identifies the toxic aldehyde acrolein as a key mediator of the observed adverse vascular consequences. Thus, e-cigarettes have the potential to induce marked adverse cardiovascular, pulmonary, and cerebrovascular consequences. Since e-cigarette use is increasing, particularly amongst youth, our data suggest that aggressive steps are warranted to limit their health risks.
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Affiliation(s)
- Marin Kuntic
- Center for Cardiology, University Medical Center, Mainz, Germany
| | - Matthias Oelze
- Center for Cardiology, University Medical Center, Mainz, Germany
| | - Sebastian Steven
- Center for Cardiology, University Medical Center, Mainz, Germany.,Center for Thrombosis and Hemostasis, University Medical Center, Mainz, German
| | | | - Paul Stamm
- Center for Cardiology, University Medical Center, Mainz, Germany
| | - Sanela Kalinovic
- Center for Cardiology, University Medical Center, Mainz, Germany
| | - Katie Frenis
- Center for Cardiology, University Medical Center, Mainz, Germany
| | | | | | | | | | - Ahmad Al Zuabi
- Center for Cardiology, University Medical Center, Mainz, Germany
| | - Vivienne Brückl
- Center for Cardiology, University Medical Center, Mainz, Germany
| | - Omar Hahad
- Center for Cardiology, University Medical Center, Mainz, Germany
| | - Steffen Daub
- Center for Cardiology, University Medical Center, Mainz, Germany
| | - Franco Varveri
- Center for Cardiology, University Medical Center, Mainz, Germany
| | - Tommaso Gori
- Center for Cardiology, University Medical Center, Mainz, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main
| | - Regina Huesmann
- Institute for Inorganic and Analytical Chemistry, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Thorsten Hoffmann
- Institute for Inorganic and Analytical Chemistry, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Frank P Schmidt
- Center for Cardiology, University Medical Center, Mainz, Germany
| | - John F Keaney
- Division of Cardiovascular Medicine, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA
| | - Andreas Daiber
- Center for Cardiology, University Medical Center, Mainz, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main
| | - Thomas Münzel
- Center for Cardiology, University Medical Center, Mainz, Germany.,Center for Thrombosis and Hemostasis, University Medical Center, Mainz, German.,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main
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23
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High-Dose Vitamin C in Advanced-Stage Cancer Patients. Nutrients 2021; 13:nu13030735. [PMID: 33652579 PMCID: PMC7996511 DOI: 10.3390/nu13030735] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 02/03/2021] [Accepted: 02/22/2021] [Indexed: 02/07/2023] Open
Abstract
High-dose intravenously administered vitamin C (IVC) is widely used in cancer patients by complementary and alternative medicine practitioners. The most frequent indications for IVC therapy result from the belief in its effectiveness as a potent anti-cancer agent which additionally enhances chemosensitivity of cancer cells and reduces chemotherapy-related toxicities and fatigue intensity. In this narrative review, we decided to deal with this issue, trying to answer the question whether there is any scientific evidence supporting the rationale for application of high-dose IVC therapy in advanced-stage cancer patients. Although results obtained from preclinical studies demonstrated that millimolar ascorbate plasma concentrations achievable only after IVC administration were cytotoxic to fast-growing malignant cells and inhibited tumor growth as well as prolonged the survival of laboratory animals, such positive effects were not found in human studies with advanced-stage cancer patients. We also have not found the rationale for the use of IVC to increase the effectiveness of chemotherapy and to reduce the chemotherapy-induced toxicity in the above mentioned group. Nevertheless, in palliative care, high-dose IVC might be considered as a therapy improving the quality of life and reducing cancer-related symptoms, such as fatigue and bone pain. However, because of the absence of placebo-controlled randomized trials on IVC efficacy in advanced-stage cancer patients, the placebo effect cannot be excluded.
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Rezk‐Hanna M, Seals DR, Rossman MJ, Gupta R, Nettle CO, Means A, Dobrin D, Cheng C, Brecht M, Mosenifar Z, Araujo JA, Benowitz NL. Ascorbic Acid Prevents Vascular Endothelial Dysfunction Induced by Electronic Hookah (Waterpipe) Vaping. J Am Heart Assoc 2021; 10:e019271. [PMID: 33615833 PMCID: PMC8174254 DOI: 10.1161/jaha.120.019271] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 01/04/2021] [Indexed: 02/07/2023]
Abstract
Background Electronic hookah (e-hookah) vaping has increased in popularity among youth, who endorse unsubstantiated claims that flavored aerosol is detoxified as it passes through water. However, e-hookahs deliver nicotine by creating an aerosol of fine and ultrafine particles and other oxidants that may reduce the bioavailability of nitric oxide and impair endothelial function secondary to formation of oxygen-derived free radicals. Methods and Results We examined the acute effects of e-hookah vaping on endothelial function, and the extent to which increased oxidative stress contributes to the vaping-induced vascular impairment. Twenty-six healthy young adult habitual hookah smokers were invited to vape a 30-minute e-hookah session to evaluate the impact on endothelial function measured by brachial artery flow-mediated dilation (FMD). To test for oxidative stress mediation, plasma total antioxidant capacity levels were measured and the effect of e-hookah vaping on FMD was examined before and after intravenous infusion of the antioxidant ascorbic acid (n=11). Plasma nicotine and exhaled carbon monoxide levels were measured before and after the vaping session. Measurements were performed before and after sham-vaping control experiments (n=10). E-hookah vaping, which increased plasma nicotine (+4.93±0.92 ng/mL, P<0.001; mean±SE) with no changes in exhaled carbon monoxide (-0.15±0.17 ppm; P=0.479), increased mean arterial pressure (11±1 mm Hg, P<0.001) and acutely decreased FMD from 5.79±0.58% to 4.39±0.46% (P<0.001). Ascorbic acid infusion, which increased plasma total antioxidant capacity 5-fold, increased FMD at baseline (5.98±0.66% versus 9.46±0.87%, P<0.001), and prevented the acute FMD impairment by e-hookah vaping (9.46±0.87% versus 8.74±0.84%, P=0.002). All parameters were unchanged during sham studies. Conclusions E-hookah vaping has adverse effects on vascular function, likely mediated by oxidative stress, which overtime could accelerate development and progression of cardiovascular disease. Registration URL: https://ClinicalTrials.gov. Unique identifier: NCT03690427.
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Affiliation(s)
| | - Douglas R. Seals
- Department of Integrative PhysiologyUniversity of Colorado BoulderBoulderCO
| | - Matthew J. Rossman
- Department of Integrative PhysiologyUniversity of Colorado BoulderBoulderCO
| | - Rajat Gupta
- Division of Cardiology Department of MedicineDavid Geffen School of Medicine at University of CaliforniaLos AngelesCA
| | | | | | - Daniel Dobrin
- School of NursingUniversity of CaliforniaLos AngelesCA
| | | | | | - Zab Mosenifar
- Division of Pulmonary and Critical Care MedicineCedars‐Sinai Medical CenterLos AngelesCA
| | - Jesus A. Araujo
- Division of Cardiology Department of MedicineDavid Geffen School of Medicine at University of CaliforniaLos AngelesCA
- Department of Environmental Health SciencesFielding School of Public HealthUniversity of CaliforniaLos AngelesCA
| | - Neal L. Benowitz
- Clinical Pharmacology Research ProgramDivision of CardiologyDepartment of MedicineUniversity of CaliforniaSan FranciscoCA
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Hashimoto H, Maruhashi T, Yamaji T, Harada T, Han Y, Takaeko Y, Kihara Y, Chayama K, Goto C, Aibara Y, Yusoff FM, Kishimoto S, Kajikawa M, Nakashima A, Higashi Y. Smoking status and endothelial function in Japanese men. Sci Rep 2021; 11:95. [PMID: 33420173 PMCID: PMC7794366 DOI: 10.1038/s41598-020-80012-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Accepted: 12/10/2020] [Indexed: 11/09/2022] Open
Abstract
It is established that smoking is a major risk factor of atherosclerosis. Endothelial dysfunction occurs in the initial step in the pathogenesis of atherosclerosis and plays a critical role in the development of atherosclerosis. The purpose of this study was to evaluate the association between smoking status and endothelial function in detail in men. We measured flow-mediated vasodilation (FMD) in 2209 Japanese men including 1181 men who had never smoked and 1028 current smokers. All of the participants were divided into five groups by smoking pack-years: never smoker group (= 0), light smoker group (> 0 to 10), moderate smoker group (> 10 to 20), heavy smoker group (> 20 to 30) and excessive smoker group (> 30). FMD significantly decreased in relation to pack-years (6.6 ± 3.4% in the never smoker group, 6.8 ± 3.0% in the light smoker group, 6.5 ± 2.9% in the moderate smoker group, 5.9 ± 2.9% in the heavy smoker group, and 4.9 ± 2.7% in the excessive smoker group; P < 0.001). After adjustment for age (≥ 65 years), body mass index, systolic blood pressure, low-density lipoprotein cholesterol, glucose, and year of recruitment, FMD was significantly smaller in the excessive smoker group than in the never smoker group as a reference group (OR 1.95, 95% CI 1.42 to 2.67; P < 0.001). These findings suggest that FMD decreases with an increase in the number of cigarettes smoked and that excessive smoking is associated with endothelial dysfunction. Cigarette smoking is harmful to vascular function in men who are heavy smokers.
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Affiliation(s)
- Haruki Hashimoto
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Tatsuya Maruhashi
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takayuki Yamaji
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takahiro Harada
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yiming Han
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yuji Takaeko
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Yasuki Kihara
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuaki Chayama
- Department of Gastroenterology and Metabolism, Institute of Biomedical and Health Sciences, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Chikara Goto
- Hiroshima International University, Hiroshima, Japan
| | - Yoshiki Aibara
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Farina Mohamad Yusoff
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Shinji Kishimoto
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Masato Kajikawa
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan
| | - Ayumu Nakashima
- Department of Stem Cell Biology and Medicine, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan
| | - Yukihito Higashi
- Department of Cardiovascular Regeneration and Medicine, Research Institute for Radiation Biology and Medicine (RIRBM), Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan. .,Division of Regeneration and Medicine, Medical Center for Translational and Clinical Research, Hiroshima University Hospital, Hiroshima, Japan.
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Cong G, Yan R, Sachdev U. Low serum vitamin C correlates with an increased risk of peripheral arterial disease in current smokers: Results from NHANES 2003-2004. INTERNATIONAL JOURNAL CARDIOLOGY HYPERTENSION 2020; 6. [PMID: 33385159 PMCID: PMC7773173 DOI: 10.1016/j.ijchy.2020.100037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
Background Cigarette smoking is one of the most critical risk factors for peripheral arterial disease (PAD) and inversely correlated Vitamin C. Here we determine whether serum vitamin C correlates with the risk of PAD, especially among current smokers. Methods A cross-sectional analysis of 2383 individuals ≥40 y was performed from the U.S. National Health and Nutrition Examination Survey (NHANES 2003–2004), including measurement of ankle-brachial index (ABI), smoking status and serum vitamin C. We examined the interactions between plasma vitamin C and exposure to smoking on the risk of PAD. Results 912 (38.2%) were current smokers while 207 participants were diagnosed with PAD based on ABI(ABI≤0.9). Current smokers in the lowest vitamin C quartile had the highest prevalence of PAD (14.1%) compared to other quartiles. However, this trend was not significant in nonsmokers. Current smokers in the lowest quartile had a 2.32-fold risk (95% CI, 1.03–5.32; P = 0.04) for PAD after weighted adjustment for potential confounders, including vitamin D and C-reactive protein. In contrast, non-smokers did not have a differing risk of PAD as a function of vitamin C (P for interaction = 0.019). Conclusions As an anti-oxidant and anti-inflammatory, low serum vitamin C appears to associates with the risk of PAD in smokers. A relationship between PAD and vitamin C in non-current smokers is not apparent. Modulating vitamin C in current smokers may help mitigate the risk of PAD and should be a target of mechanistic study.
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Affiliation(s)
- Guangzhi Cong
- Department of Cardiology, Cardiovascular Institute, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, CN 750004, China
| | - Ru Yan
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Ulka Sachdev
- Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
- Corresponding author. Magee Womens Hospital of UPMC, 300 Halket Street Suite 5414, Pittsburgh, 15232, PA, China.
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Vitamin C and Cardiovascular Disease: An Update. Antioxidants (Basel) 2020; 9:antiox9121227. [PMID: 33287462 PMCID: PMC7761826 DOI: 10.3390/antiox9121227] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 11/24/2020] [Accepted: 11/27/2020] [Indexed: 02/07/2023] Open
Abstract
The potential beneficial effects of the antioxidant properties of vitamin C have been investigated in a number of pathological conditions. In this review, we assess both clinical and preclinical studies evaluating the role of vitamin C in cardiac and vascular disorders, including coronary heart disease, heart failure, hypertension, and cerebrovascular diseases. Pitfalls and controversies in investigations on vitamin C and cardiovascular disorders are also discussed.
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28
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Reina-Torres E, De Ieso ML, Pasquale LR, Madekurozwa M, van Batenburg-Sherwood J, Overby DR, Stamer WD. The vital role for nitric oxide in intraocular pressure homeostasis. Prog Retin Eye Res 2020; 83:100922. [PMID: 33253900 DOI: 10.1016/j.preteyeres.2020.100922] [Citation(s) in RCA: 54] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 11/13/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023]
Abstract
Catalyzed by endothelial nitric oxide (NO) synthase (eNOS) activity, NO is a gaseous signaling molecule maintaining endothelial and cardiovascular homeostasis. Principally, NO regulates the contractility of vascular smooth muscle cells and permeability of endothelial cells in response to either biochemical or biomechanical cues. In the conventional outflow pathway of the eye, the smooth muscle-like trabecular meshwork (TM) cells and Schlemm's canal (SC) endothelium control aqueous humor outflow resistance, and therefore intraocular pressure (IOP). The mechanisms by which outflow resistance is regulated are complicated, but NO appears to be a key player as enhancement or inhibition of NO signaling dramatically affects outflow function; and polymorphisms in NOS3, the gene that encodes eNOS modifies the relation between various environmental exposures and glaucoma. Based upon a comprehensive review of past foundational studies, we present a model whereby NO controls a feedback signaling loop in the conventional outflow pathway that is sensitive to changes in IOP and its oscillations. Thus, upon IOP elevation, the outflow pathway tissues distend, and the SC lumen narrows resulting in increased SC endothelial shear stress and stretch. In response, SC cells upregulate the production of NO, relaxing neighboring TM cells and increasing permeability of SC's inner wall. These IOP-dependent changes in the outflow pathway tissues reduce the resistance to aqueous humor drainage and lower IOP, which, in turn, diminishes the biomechanical signaling on SC. Similar to cardiovascular pathogenesis, dysregulation of the eNOS/NO system leads to dysfunctional outflow regulation and ocular hypertension, eventually resulting in primary open-angle glaucoma.
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Affiliation(s)
| | | | - Louis R Pasquale
- Eye and Vision Research Institute of New York Eye and Ear Infirmary at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | | | - Darryl R Overby
- Department of Bioengineering, Imperial College London, London, UK.
| | - W Daniel Stamer
- Department of Ophthalmology, Duke University, Durham, NC, USA.
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29
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Münzel T, Hahad O, Kuntic M, Keaney JF, Deanfield JE, Daiber A. Effects of tobacco cigarettes, e-cigarettes, and waterpipe smoking on endothelial function and clinical outcomes. Eur Heart J 2020; 41:4057-4070. [PMID: 32585699 PMCID: PMC7454514 DOI: 10.1093/eurheartj/ehaa460] [Citation(s) in RCA: 219] [Impact Index Per Article: 43.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 04/24/2020] [Accepted: 05/14/2020] [Indexed: 12/13/2022] Open
Abstract
Tobacco smoking is a leading cause of non-communicable disease globally and is a major risk factor for cardiovascular disease (CVD) and lung disease. Importantly, recent data by the World Health Organizations (WHO) indicate that in the last two decades global tobacco use has significantly dropped, which was largely driven by decreased numbers of female smokers. Despite such advances, the use of e-cigarettes and waterpipes (shisha, hookah, narghile) is an emerging trend, especially among younger generations. There is growing body of evidence that e-cigarettes are not a harm-free alternative to tobacco cigarettes and there is considerable debate as to whether e-cigarettes are saving smokers or generating new addicts. Here, we provide an updated overview of the impact of tobacco/waterpipe (shisha) smoking and e-cigarette vaping on endothelial function, a biomarker for early, subclinical, atherosclerosis from human and animal studies. Also their emerging adverse effects on the proteome, transcriptome, epigenome, microbiome, and the circadian clock are summarized. We briefly discuss heat-not-burn tobacco products and their cardiovascular health effects. We discuss the impact of the toxic constituents of these products on endothelial function and subsequent CVD and we also provide an update on current recommendations, regulation and advertising with focus on the USA and Europe. As outlined by the WHO, tobacco cigarette, waterpipe, and e-cigarette smoking/vaping may contribute to an increased burden of symptoms due to coronavirus disease 2019 (COVID-19) and to severe health consequences.
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Affiliation(s)
- Thomas Münzel
- Center for Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Langenbeckstraße 1, 55131 Mainz, Germany
| | - Omar Hahad
- Center for Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Langenbeckstraße 1, 55131 Mainz, Germany
| | - Marin Kuntic
- Center for Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany
| | - John F Keaney
- Division of Cardiovascular Medicine, University of Massachusetts Medical School, 55 Lake Avenue North, Worcester, MA 01655, USA
| | - John E Deanfield
- Institute of Cardiovascular Science, University College London, 1 St Martin's le Grand, London EC1A 4NP, UK
| | - Andreas Daiber
- Center for Cardiology-Cardiology I, University Medical Center of the Johannes Gutenberg-University Mainz, Langenbeckstraße 1, 55131 Mainz, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Langenbeckstraße 1, 55131 Mainz, Germany
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30
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Berretta M, Quagliariello V, Maurea N, Di Francia R, Sharifi S, Facchini G, Rinaldi L, Piezzo M, Manuela C, Nunnari G, Montopoli M. Multiple Effects of Ascorbic Acid against Chronic Diseases: Updated Evidence from Preclinical and Clinical Studies. Antioxidants (Basel) 2020; 9:antiox9121182. [PMID: 33256059 PMCID: PMC7761324 DOI: 10.3390/antiox9121182] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/18/2020] [Accepted: 11/19/2020] [Indexed: 12/12/2022] Open
Abstract
Severe disease commonly manifests as a systemic inflammatory process. Inflammation is associated withthe enhanced production of reactive oxygen and nitrogen species and with a marked reduction in the plasma concentrations of protective antioxidant molecules. This imbalance gives rise to oxidative stress, which is greater in patients with more severe conditions such as sepsis, cancer, cardiovascular disease, acute respiratory distress syndrome, and burns. In these patients, oxidative stress can trigger cell, tissue, and organ damage, thus increasing morbidity and mortality. Ascorbic acid (ASC) is a key nutrient thatserves as an antioxidant and a cofactor for numerous enzymatic reactions. However, humans, unlike most mammals, are unable to synthesize it. Consequently, ASC must be obtained through dietary sources, especially fresh fruit and vegetables. The value of administering exogenous micronutrients, to reestablish antioxidant concentrations in patients with severe disease, has been recognized for decades. Despite the suggestion that ASC supplementation may reduce oxidative stress and prevent several chronic conditions, few large, randomized clinical trials have tested it in patients with severe illness. This article reviews the recent literature on the pharmacological profile of ASC and the role of its supplementation in critically ill patients.
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Affiliation(s)
- Massimiliano Berretta
- Department of Clinical and Experimental Medicine, University of Messina, 98121 Messina, Italy;
- Correspondence:
| | - Vincenzo Quagliariello
- Division of Cardiology, Istituto Nazionale Tumori—IRCCS Fondazione “G. Pascale”, 80131 Napoli, Italy; (V.Q.); (N.M.)
| | - Nicola Maurea
- Division of Cardiology, Istituto Nazionale Tumori—IRCCS Fondazione “G. Pascale”, 80131 Napoli, Italy; (V.Q.); (N.M.)
| | - Raffaele Di Francia
- Italian Association of Pharmacogenomics and Molecular Diagnostics (IAPharmagen), 60126 Ancona, Italy;
| | - Saman Sharifi
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35100 Padova, Italy; (S.S.); (M.M.)
| | - Gaetano Facchini
- Division of Medical Oncology, “S. Maria delle Grazie” Hospital—ASL Napoli 2 Nord, 80126 Pozzuoli, Italy;
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania “L. Vanvitelli”, 80121 Napoli, Italy;
| | - Michela Piezzo
- Division of Breast Medical Oncology, Istituto Nazionale Tumori—IRCCS Fondazione “G. Pascale”, 80131 Napoli, Italy;
| | - Ceccarelli Manuela
- Division of Infectious Disease, University of Catania, 95122 Catania, Italy;
| | - Giuseppe Nunnari
- Department of Clinical and Experimental Medicine, University of Messina, 98121 Messina, Italy;
| | - Monica Montopoli
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, 35100 Padova, Italy; (S.S.); (M.M.)
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Haptonstall KP, Choroomi Y, Moheimani R, Nguyen K, Tran E, Lakhani K, Ruedisueli I, Gornbein J, Middlekauff HR. Differential effects of tobacco cigarettes and electronic cigarettes on endothelial function in healthy young people. Am J Physiol Heart Circ Physiol 2020; 319:H547-H556. [PMID: 32734819 DOI: 10.1152/ajpheart.00307.2020] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Tobacco cigarette (TC) smoking has never been lower in the United States, but electronic cigarette (EC) vaping has reached epidemic proportions among our youth. Endothelial dysfunction, as measured by flow-mediated vasodilation (FMD) is a predictor of future atherosclerosis and adverse cardiovascular events and is impaired in young TC smokers, but whether FMD is also reduced in young EC vapers is uncertain. The aim of this study in otherwise healthy young people was to compare the effects of acute and chronic tobacco cigarette (TC) smoking and electronic cigarette (EC) vaping on FMD. FMD was compared in 47 nonsmokers (NS), 49 chronic EC vapers, and 40 chronic TC smokers at baseline and then after EC vapers (n = 31) and nonsmokers (n = 47) acutely used an EC with nicotine (ECN), EC without nicotine (EC0), and nicotine inhaler (NI) at ~4-wk intervals and after TC smokers (n = 33) acutely smoked a TC, compared with sham control. Mean age (NS, 26.3 ± 5.2 vs. EC, 27.4 ± 5.45 vs. TC, 27.1 ± 5.51 yr, P = 0.53) was similar among the groups, but there were more female nonsmokers. Baseline FMD was not different among the groups (NS, 7.7 ± 4.5 vs. EC:6.6 ± 3.6 vs. TC, 7.9 ± 3.7%∆, P = 0.35), even when compared by group and sex. Acute TC smoking versus control impaired FMD (FMD pre-/postsmoking, -2.52 ± 0.92 vs. 0.65 ± 0.93%∆, P = 0.02). Although the increase in plasma nicotine was similar after EC vapers used the ECN versus TC smokers smoked the TC (5.75 ± 0.74 vs. 5.88 ± 0.69 ng/mL, P = 0.47), acute EC vaping did not impair FMD. In otherwise healthy young people who regularly smoke TCs or ECs, impaired FMD compared with that in nonsmokers was not present at baseline. However, FMD was significantly impaired after smoking one TC, but not after vaping an equivalent "dose" (estimated by change in plasma nicotine) of an EC, consistent with the notion that non-nicotine constituents in TC smoke mediate the impairment. Although it is reassuring that acute EC vaping did not acutely impair FMD, it would be dangerous and premature to conclude that ECs do not lead to atherosclerosis.NEW & NOTEWORTHY In our study of otherwise healthy young people, baseline flow-mediated dilation (FMD), a predictor of atherosclerosis and increased cardiovascular risk, was not different among tobacco cigarette (TC) smokers or electronic cigarette (EC) vapers who had refrained from smoking, compared with nonsmokers. However, acutely smoking one TC impaired FMD in smokers, whereas vaping a similar EC "dose" (as estimated by change in plasma nicotine levels) did not. Finally, although it is reassuring that acute EC vaping did not acutely impair FMD, it would be premature and dangerous to conclude that ECs do not lead to atherosclerosis or increase cardiovascular risk.
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Affiliation(s)
- Kacey P Haptonstall
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California
| | - Yasmine Choroomi
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California
| | - Roya Moheimani
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California
| | - Kevin Nguyen
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California
| | - Elizabeth Tran
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California
| | - Karishma Lakhani
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California
| | - Isabella Ruedisueli
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California
| | - Jeffrey Gornbein
- Departments of Medicine and Computational Medicine, David Geffen School of Medicine at University of California, Los Angeles, California
| | - Holly R Middlekauff
- Division of Cardiology, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California
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Roumeliotis S, Mallamaci F, Zoccali C. Endothelial Dysfunction in Chronic Kidney Disease, from Biology to Clinical Outcomes: A 2020 Update. J Clin Med 2020; 9:jcm9082359. [PMID: 32718053 PMCID: PMC7465707 DOI: 10.3390/jcm9082359] [Citation(s) in RCA: 150] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Revised: 07/20/2020] [Accepted: 07/21/2020] [Indexed: 02/06/2023] Open
Abstract
The vascular endothelium is a dynamic, functionally complex organ, modulating multiple biological processes, including vascular tone and permeability, inflammatory responses, thrombosis, and angiogenesis. Endothelial dysfunction is a threat to the integrity of the vascular system, and it is pivotal in the pathogenesis of atherosclerosis and cardiovascular disease. Reduced nitric oxide (NO) bioavailability is a hallmark of chronic kidney disease (CKD), with this disturbance being almost universal in patients who reach the most advanced phase of CKD, end-stage kidney disease (ESKD). Low NO bioavailability in CKD depends on several mechanisms affecting the expression and the activity of endothelial NO synthase (eNOS). Accumulation of endogenous inhibitors of eNOS, inflammation and oxidative stress, advanced glycosylation products (AGEs), bone mineral balance disorders encompassing hyperphosphatemia, high levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23), and low levels of the active form of vitamin D (1,25 vitamin D) and the anti-ageing vasculoprotective factor Klotho all impinge upon NO bioavailability and are critical to endothelial dysfunction in CKD. Wide-ranging multivariate interventions are needed to counter endothelial dysfunction in CKD, an alteration triggering arterial disease and cardiovascular complications in this high-risk population.
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Affiliation(s)
- Stefanos Roumeliotis
- Division of Nephrology and Hypertension, 1st Department of Internal Medicine, School of Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, 54636 Thessaloniki, Greece;
| | - Francesca Mallamaci
- CNR-IFC (National Research Council of Italy, Centre of Clinical Physiology, Clinical Epidemiology of Renal Diseases and Hypertension Unit, Reggio Cal., c/o Ospedali Riuniti, 89124 Reggio Cal, Italy;
| | - Carmine Zoccali
- CNR-IFC (National Research Council of Italy, Centre of Clinical Physiology, Clinical Epidemiology of Renal Diseases and Hypertension Unit, Reggio Cal., c/o Ospedali Riuniti, 89124 Reggio Cal, Italy;
- Correspondence: ; Tel.: +39-340-73540-62
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Münzel T, Daiber A. Novel Concept for the Regulation of eNOS (Endothelial Nitric Oxide Synthase) Activity: Inhibitory Effects of the Enigma Homolog Protein and the PHLPP (Pleckstrin Homology Domain and Leucine-Rich Repeat Protein Phosphatase)-2 on Akt (Protein Kinase B)-Dependent Nitric Oxide Synthase Activation. Arterioscler Thromb Vasc Biol 2020; 40:1608-1610. [PMID: 32579479 DOI: 10.1161/atvbaha.120.314474] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
- Thomas Münzel
- From the Center for Cardiology, Cardiology I (T.M., A.D.), University Medical Center Mainz, Germany.,Center for Thrombosis and Hemostasis (CTH) (T.M.), University Medical Center Mainz, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany (T.M., A.D.)
| | - Andreas Daiber
- From the Center for Cardiology, Cardiology I (T.M., A.D.), University Medical Center Mainz, Germany.,German Center for Cardiovascular Research (DZHK), Partner Site Rhine-Main, Mainz, Germany (T.M., A.D.)
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Matsuoka T, Shinozaki H, Ozawa S, Izawa Y, Koyanagi K, Kawarai Lefor A, Kobayashi K. Administration of Corticosteroids, Ascorbic Acid, and Thiamine Improves Oxygenation after Thoracoscopic Esophagectomy. Ann Thorac Cardiovasc Surg 2020; 26:133-139. [PMID: 31631076 PMCID: PMC7303314 DOI: 10.5761/atcs.oa.19-00202] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Accepted: 09/12/2019] [Indexed: 12/11/2022] Open
Abstract
PURPOSE The activity of corticosteroids, ascorbic acid, and thiamine against oxidative and inflammatory responses was evaluated in patients undergoing esophagectomy. This study was undertaken to investigate the effect of this combined therapy on lung dysfunction following esophagectomy. METHODS In this retrospective before-after study, we compared the clinical course of consecutive patients undergoing thoracoscopic esophagectomy treated with the combination of corticosteroids, ascorbic acid, and thiamine between June and December 2018 with a control group treated with corticosteroids alone between January 2016 and May 2018. Outcomes included oxygenation (arterial partial pressure of oxygen (PaO2)/fractional concentration of inspired oxygen (FiO2) ratios), duration of mechanical ventilation and intensive care unit (ICU) length of stay. RESULTS In all, 17 patients were included in this study (6 in the combination therapy group and 11 patients in the control group). Mean PaO2/FiO2 ratios in the combined therapy group were significantly higher than in the control group at all points during the observation period (p <0.001). In the combined therapy group, the duration of mechanical ventilation and ICU stay were significantly shorter (p <0.001, p = 0.009). CONCLUSIONS This study suggests that combined therapy including corticosteroids, ascorbic acid, and thiamine may be effective in improving oxygenation after esophagectomy. Additional studies are required to confirm these preliminary findings.
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Affiliation(s)
- Tadashi Matsuoka
- Department of Surgery, Saiseikai Utsunomiya Hospital, Utsunomiya, Tochigi, Japan
| | - Hiroharu Shinozaki
- Department of Surgery, Saiseikai Utsunomiya Hospital, Utsunomiya, Tochigi, Japan
| | - Soji Ozawa
- Department of Gastroenterological Surgery, School of Medicine, Tokai University, Isehara, Kanagawa, Japan
| | - Yoshimitsu Izawa
- Department of Surgery, Saiseikai Utsunomiya Hospital, Utsunomiya, Tochigi, Japan
| | - Kazuo Koyanagi
- Department of Gastroenterological Surgery, School of Medicine, Tokai University, Isehara, Kanagawa, Japan
| | - Alan Kawarai Lefor
- Department of Surgery, Jichi Medical University, Shimotsuke, Tochigi, Japan
| | - Kenji Kobayashi
- Department of Surgery, Saiseikai Utsunomiya Hospital, Utsunomiya, Tochigi, Japan
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El-Mahdy MA, Abdelghany TM, Hemann C, Ewees MG, Mahgoup EM, Eid MS, Shalaan MT, Alzarie YA, Zweier JL. Chronic cigarette smoke exposure triggers a vicious cycle of leukocyte and endothelial-mediated oxidant stress that results in vascular dysfunction. Am J Physiol Heart Circ Physiol 2020; 319:H51-H65. [PMID: 32412791 DOI: 10.1152/ajpheart.00657.2019] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Although there is a strong association between cigarette smoking exposure (CSE) and vascular endothelial dysfunction (VED), the underlying mechanisms by which CSE triggers VED remain unclear. Therefore, studies were performed to define these mechanisms using a chronic mouse model of cigarette smoking (CS)-induced cardiovascular disease mirroring that in humans. C57BL/6 male mice were subjected to CSE for up to 48 wk. CSE impaired acetylcholine (ACh)-induced relaxation of aortic and mesenteric segments and triggered hypertension, with mean arterial blood pressure at 32 and 48 wk of exposure of 122 ± 6 and 135 ± 5 mmHg compared with 99 ± 4 and 102 ± 6 mmHg, respectively, in air-exposed mice. CSE led to monocyte activation with superoxide generation in blood exiting the pulmonary circulation. Macrophage infiltration with concomitant increase in NADPH oxidase subunits p22phox and gp91phox was seen in aortas of CS-exposed mice at 16 wk, with further increase out to 48 wk. Associated with this, increased superoxide production was detected that decreased with Nox inhibition. Tetrahydrobiopterin was progressively depleted in CS-exposed mice but not in air-exposed controls, resulting in endothelial nitric oxide synthase (eNOS) uncoupling and secondary superoxide generation. CSE led to a time-dependent decrease in eNOS and Akt expression and phosphorylation. Overall, CSE induces vascular monocyte infiltration with increased NADPH oxidase-mediated reactive oxygen species generation and depletes the eNOS cofactor tetrahydrobiopterin, uncoupling eNOS and triggering a vicious cycle of oxidative stress with VED and hypertension. Our study provides important insights toward understanding the process by which smoking contributes to the genesis of cardiovascular disease and identifies biomarkers predictive of disease.NEW & NOTEWORTHY In a chronic model of smoking-induced cardiovascular disease, we define underlying mechanisms of smoking-induced vascular endothelial dysfunction (VED). Smoking exposure triggered VED and hypertension and led to vascular macrophage infiltration with concomitant increase in superoxide and NADPH oxidase levels as early as 16 wk of exposure. This oxidative stress was accompanied by tetrahydrobiopterin depletion, resulting in endothelial nitric oxide synthase uncoupling with further superoxide generation triggering a vicious cycle of oxidative stress and VED.
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Affiliation(s)
- Mohamed A El-Mahdy
- Division of Cardiovascular Medicine, Department of Internal Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio
| | - Tamer M Abdelghany
- Division of Cardiovascular Medicine, Department of Internal Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio.,Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Craig Hemann
- Division of Cardiovascular Medicine, Department of Internal Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio
| | - Mohamed G Ewees
- Division of Cardiovascular Medicine, Department of Internal Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio.,Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Elsayed M Mahgoup
- Division of Cardiovascular Medicine, Department of Internal Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio.,Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Mahmoud S Eid
- Division of Cardiovascular Medicine, Department of Internal Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio.,Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Mahmoud T Shalaan
- Division of Cardiovascular Medicine, Department of Internal Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio.,Department of Pharmacology and Toxicology, College of Pharmacy, Al-Azhar University, Cairo, Egypt
| | - Yasmin A Alzarie
- Division of Cardiovascular Medicine, Department of Internal Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio.,Department of Pharmacology and Toxicology, College of Pharmacy, Helwan University, National Organization of Drug Control and Research, Cairo, Egypt
| | - Jay L Zweier
- Division of Cardiovascular Medicine, Department of Internal Medicine, Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University, Columbus, Ohio
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36
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Affiliation(s)
- Thomas Münzel
- University Medical Center Mainz, Center for Cardiology, Cardiology I, Mainz, Germany
| | - Omar Hahad
- University Medical Center Mainz, Center for Cardiology, Cardiology I, Mainz, Germany
| | - Andreas Daiber
- University Medical Center Mainz, Center for Cardiology, Cardiology I, Mainz, Germany
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37
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West S, Smail O, Bond B. The acute influence of sucrose consumption with and without vitamin C co-ingestion on microvascular reactivity in healthy young adults. Microvasc Res 2019; 126:103906. [DOI: 10.1016/j.mvr.2019.103906] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 07/15/2019] [Accepted: 07/17/2019] [Indexed: 02/07/2023]
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Rodriguez-Portelles A, Rodriguez-Leyva D. Endothelial and left ventricular diastolic function in young adults exposed to tobacco. Can J Physiol Pharmacol 2019; 97:1006-1011. [PMID: 31269406 DOI: 10.1139/cjpp-2019-0187] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Smoking is associated with endothelial and left ventricular diastolic disfunction. We aimed to determine the endothelial and diastolic function in young adults exposed to tobacco smoke and the effects of acute exposure to it. Smokers were considered as cases and non-smokers as controls. Brachial artery diameter, brachial artery flow velocity, and echocardiographic variables were measured. Mean age of the participants was 21 years. Smokers showed significant endothelial dysfunction compared with non-smokers. Arterial dilation mediated by the endothelium was significantly higher in non-smokers than in smokers (p = 0.005). Non-endothelium-mediated arterial dilation was significantly impaired in smokers compared with non-smokers (p = 0.02). After reactive hyperaemia, there was a significant increase in blood flow in non-smokers (61%) compared with that in smokers (29%). Acute cigarette exposure showed a trend towards left ventricle diastolic disfunction in smokers. Left atrium diameter was significantly higher in smokers than in non-smokers. After acute exposure to cigarette smoke, arterial dilation and brachial flow velocity were lower than those achieved in the abstinence phase (p = 0.005). We concluded that endothelium-dependent arterial dilation is impaired in young smokers and it worsens even after acute exposure to cigarette smoke.
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Affiliation(s)
- Ayelen Rodriguez-Portelles
- Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, Winnipeg, MB R2H 2A6, Canada
| | - Delfin Rodriguez-Leyva
- Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, Winnipeg, MB R2H 2A6, Canada
- Department of Physiology and Pathophysiology, Department of Internal Medicine, Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0W2, Canada
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Nanotherapies for Treatment of Cardiovascular Disease: A Case for Antioxidant Targeted Delivery. CURRENT PATHOBIOLOGY REPORTS 2019; 7:47-60. [PMID: 31396435 DOI: 10.1007/s40139-019-00196-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Purpose of Review Cardiovascular disease (CVD) involves a broad range of clinical manifestations resulting from a dysfunctional vascular system. Overproduction of reactive oxygen and nitrogen species are causally implicated in the severity of vascular dysfunction and CVD. Antioxidant therapy is an attractive avenue for treatment of CVD associated pathologies. Implementation of targeted nano-antioxidant therapies has the potential to overcome hurdles associated with systemic delivery of antioxidants. This review examines the currently available options for nanotherapeutic targeting CVD, and explores successful studies showcasing targeted nano-antioxidant therapy. Recent Findings Active targeting strategies in the context of CVD heavily focus on immunotargeting to inflammatory markers like cell adhesion molecules, or to exposed extracellular matrix components. Targeted antioxidant nanotherapies have found success in pre-clinical studies. Summary This review underscores the potential of targeted nanocarriers as means of finding success translating antioxidant therapies to the clinic, all with a focus on CVD.
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40
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Conklin DJ, Schick S, Blaha MJ, Carll A, DeFilippis A, Ganz P, Hall ME, Hamburg N, O'Toole T, Reynolds L, Srivastava S, Bhatnagar A. Cardiovascular injury induced by tobacco products: assessment of risk factors and biomarkers of harm. A Tobacco Centers of Regulatory Science compilation. Am J Physiol Heart Circ Physiol 2019; 316:H801-H827. [PMID: 30707616 PMCID: PMC6483019 DOI: 10.1152/ajpheart.00591.2018] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Revised: 01/09/2019] [Accepted: 01/27/2019] [Indexed: 02/07/2023]
Abstract
Although substantial evidence shows that smoking is positively and robustly associated with cardiovascular disease (CVD), the CVD risk associated with the use of new and emerging tobacco products, such as electronic cigarettes, hookah, and heat-not-burn products, remains unclear. This uncertainty stems from lack of knowledge on how the use of these products affects cardiovascular health. Cardiovascular injury associated with the use of new tobacco products could be evaluated by measuring changes in biomarkers of cardiovascular harm that are sensitive to the use of combustible cigarettes. Such cardiovascular injury could be indexed at several levels. Preclinical changes contributing to the pathogenesis of disease could be monitored by measuring changes in systemic inflammation and oxidative stress, organ-specific dysfunctions could be gauged by measuring endothelial function (flow-mediated dilation), platelet aggregation, and arterial stiffness, and organ-specific injury could be evaluated by measuring endothelial microparticles and platelet-leukocyte aggregates. Classical risk factors, such as blood pressure, circulating lipoproteins, and insulin resistance, provide robust estimates of risk, and subclinical disease progression could be followed by measuring coronary artery Ca2+ and carotid intima-media thickness. Given that several of these biomarkers are well-established predictors of major cardiovascular events, the association of these biomarkers with the use of new and emerging tobacco products could be indicative of both individual and population-level CVD risk associated with the use of these products. Differential effects of tobacco products (conventional vs. new and emerging products) on different indexes of cardiovascular injury could also provide insights into mechanisms by which they induce cardiovascular harm.
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Affiliation(s)
- Daniel J Conklin
- Diabetes and Obesity Center, University of Louisville , Louisville, Kentucky
| | - Suzaynn Schick
- Department of Medicine, University of California-San Francisco , San Francisco, California
| | - Michael J Blaha
- Ciccarone Center for the Prevention of Heart Disease, Department of Medicine, Johns Hopkins University , Baltimore, Maryland
| | - Alex Carll
- Diabetes and Obesity Center, University of Louisville , Louisville, Kentucky
| | - Andrew DeFilippis
- Diabetes and Obesity Center, University of Louisville , Louisville, Kentucky
| | - Peter Ganz
- Department of Medicine, University of California-San Francisco , San Francisco, California
| | - Michael E Hall
- Department of Physiology and Biophysics, University of Mississippi Medical Center , Jackson, Mississippi
| | - Naomi Hamburg
- Department of Medicine/Cardiovascular Medicine, School of Medicine, Boston University , Boston, Massachusetts
| | - Tim O'Toole
- Diabetes and Obesity Center, University of Louisville , Louisville, Kentucky
| | - Lindsay Reynolds
- Department of Epidemiology and Prevention, Wake Forest School of Medicine , Winston-Salem, North Carolina
| | - Sanjay Srivastava
- Diabetes and Obesity Center, University of Louisville , Louisville, Kentucky
| | - Aruni Bhatnagar
- Diabetes and Obesity Center, University of Louisville , Louisville, Kentucky
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41
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Xia N, Morteza A, Yang F, Cao H, Wang A. Review of the role of cigarette smoking in diabetic foot. J Diabetes Investig 2019; 10:202-215. [PMID: 30300476 PMCID: PMC6400172 DOI: 10.1111/jdi.12952] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 09/11/2018] [Accepted: 09/30/2018] [Indexed: 12/13/2022] Open
Abstract
Diabetic foot ulceration has been a serious issue over the past decades in Asia, causing economic and social problems. Therefore, it is important to identify and reduce the risk factors of diabetic foot. Cigarette smoking has been reported to be associated with diabetes and its macrovascular complications, but the relationship between smoking and diabetic foot ulcers is still unclear. In the present review, we summarize the effects of cigarette smoking on diabetic foot ulcers with respect to peripheral neuropathy, vascular alterations and wound healing. One underlying mechanism of these impacts might be the smoking-induced oxidative stress inside the cells. At the end of this review, the current mainstream therapies for smoking cessation are also outlined. We believe that it is urgent for all diabetic patients to quit smoking so as to reduce their chances of developing foot ulcers and to improve the prognosis of diabetic foot ulcers.
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Affiliation(s)
- Nan Xia
- Diabetes & Wound Care CenterMingci Cardiovascular HospitalWuxiChina
| | - Afsaneh Morteza
- Endocrinology and Metabolism Research Center – EMRCVali‐Asr. HospitalTehran University of Medical SciencesTehranIran
| | - Fengyu Yang
- Diabetes & Wound Care CenterMingci Cardiovascular HospitalWuxiChina
| | - Hong Cao
- Department of EndocrinologyWuxi No. 3 People's HospitalWuxiChina
| | - Aiping Wang
- Diabetes & Wound Care CenterMingci Cardiovascular HospitalWuxiChina
- Department of EndocrinologyNanjing 454th HospitalNanjingChina
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42
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Kwon JH, Kim D, Cho H, Shin BS. Ascorbic acid improves thrombotic function of platelets during living donor liver transplantation by modulating the function of the E3 ubiquitin ligases c-Cbl and Cbl-b. J Int Med Res 2019; 47:1856-1867. [PMID: 30614340 PMCID: PMC6567784 DOI: 10.1177/0300060518817408] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
OBJECTIVE To investigate the effect of ascorbic acid (AA) on hemostatic function during living donor liver transplantation (LDLT). METHODS Blood samples from 21 LDLT recipients were taken within 30 minutes after induction and at 120 minutes after reperfusion. Rotational thromboelastography (TEG) and western blot analysis were used to analyze for fibrinolysis and functional changes in c-Cbl and Cbl-b, respectively. TEG test samples were prepared as one of three groups: C group (0.36 mL of blood), N group (0.324 mL of blood + 0.036 mL of 0.9% normal saline), and A group (0.324 mL of blood + 0.036 mL of 200 µmol/L-AA dissolved in 0.9% normal saline). RESULTS AA decreased fibrinolysis and increased clot rigidity at baseline and 120 minutes after reperfusion. Cbl-b expression was significantly increased at baseline and 120 minutes after reperfusion in the A group compared with the C and N groups. However, c-Cbl phosphorylation was most significantly decreased in the A group at baseline and 120 minutes after reperfusion. CONCLUSION AA can significantly decrease fibrinolysis and improve clot rigidity in LT recipients during LDLT, and functional changes in Cbl-b and c-Cbl might represent the underlying mechanism. AA may be considered for use during LDLT to decrease hyperfibrinolysis.
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Affiliation(s)
- Ji Hye Kwon
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea
| | - Doyeon Kim
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea
| | - Hyojin Cho
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea
| | - Byung Seop Shin
- Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University, School of Medicine, Seoul, Korea
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43
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Tejero J, Shiva S, Gladwin MT. Sources of Vascular Nitric Oxide and Reactive Oxygen Species and Their Regulation. Physiol Rev 2019; 99:311-379. [PMID: 30379623 PMCID: PMC6442925 DOI: 10.1152/physrev.00036.2017] [Citation(s) in RCA: 330] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 03/30/2018] [Accepted: 05/06/2018] [Indexed: 02/07/2023] Open
Abstract
Nitric oxide (NO) is a small free radical with critical signaling roles in physiology and pathophysiology. The generation of sufficient NO levels to regulate the resistance of the blood vessels and hence the maintenance of adequate blood flow is critical to the healthy performance of the vasculature. A novel paradigm indicates that classical NO synthesis by dedicated NO synthases is supplemented by nitrite reduction pathways under hypoxia. At the same time, reactive oxygen species (ROS), which include superoxide and hydrogen peroxide, are produced in the vascular system for signaling purposes, as effectors of the immune response, or as byproducts of cellular metabolism. NO and ROS can be generated by distinct enzymes or by the same enzyme through alternate reduction and oxidation processes. The latter oxidoreductase systems include NO synthases, molybdopterin enzymes, and hemoglobins, which can form superoxide by reduction of molecular oxygen or NO by reduction of inorganic nitrite. Enzymatic uncoupling, changes in oxygen tension, and the concentration of coenzymes and reductants can modulate the NO/ROS production from these oxidoreductases and determine the redox balance in health and disease. The dysregulation of the mechanisms involved in the generation of NO and ROS is an important cause of cardiovascular disease and target for therapy. In this review we will present the biology of NO and ROS in the cardiovascular system, with special emphasis on their routes of formation and regulation, as well as the therapeutic challenges and opportunities for the management of NO and ROS in cardiovascular disease.
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Affiliation(s)
- Jesús Tejero
- Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh , Pittsburgh, Pennsylvania ; Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania ; Department of Pharmacology and Chemical Biology, University of Pittsburgh , Pittsburgh, Pennsylvania ; and Department of Medicine, Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
| | - Sruti Shiva
- Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh , Pittsburgh, Pennsylvania ; Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania ; Department of Pharmacology and Chemical Biology, University of Pittsburgh , Pittsburgh, Pennsylvania ; and Department of Medicine, Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
| | - Mark T Gladwin
- Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh , Pittsburgh, Pennsylvania ; Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania ; Department of Pharmacology and Chemical Biology, University of Pittsburgh , Pittsburgh, Pennsylvania ; and Department of Medicine, Center for Metabolism and Mitochondrial Medicine, University of Pittsburgh , Pittsburgh, Pennsylvania
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44
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Affiliation(s)
- Jessica L Fetterman
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
| | - Naomi M Hamburg
- Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA
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Ascorbate Attenuates Oxidative Stress and Increased Blood Pressure Induced by 2-(4-Hydroxyphenyl) Amino-1,4-naphthoquinone in Rats. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:8989676. [PMID: 30147836 PMCID: PMC6083601 DOI: 10.1155/2018/8989676] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Revised: 05/15/2018] [Accepted: 06/07/2018] [Indexed: 11/30/2022]
Abstract
Quinone derivatives like 2-(4-hydroxyphenyl) amino-1,4-naphthoquinone (Q7) are used as antitumor agents usually associated with adverse effects on the cardiovascular system. The objective of this study was to evaluate the cardioprotective effect of ascorbate on Q7-induced cardiovascular response in Wistar rats. In this study, blood pressure, vascular reactivity, and intracellular calcium fluxes were evaluated in cardiomyocytes and the rat aorta. We also measured oxidative stress through lipid peroxidation (TBARS), superoxide dismutase- (SOD-) like activity, and H2O2 generation. Oral treatment of rats with ascorbate (500 mg/kg) for 20 days significantly (p < 0.05) reduced the Q7-induced increase (10 mg/kg) in blood pressure and heart rate. The preincubation with ascorbate (2 mM) significantly (p < 0.05) attenuated the irregular beating of the atrium induced by Q7 (10−5 M). In addition, ascorbate induced endothelial vasodilation in the presence of Q7 in the intact aortic rings of a rat and reduced the cytosolic calcium levels in vascular smooth muscle cells. Ascorbate also reduced the Q7-induced oxidative stress in vivo. Ascorbate also attenuated Q7-induced SOD-like activity and increased TBARS levels. These results suggest a cardioprotective effect in vivo of ascorbate in animals treated orally with a naphthoquinone derivative by a mechanism involving oxidative stress.
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46
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The mechanistic role of oxidative stress in cigarette smoke-induced cardiac stem cell dysfunction and prevention by ascorbic acid. Cell Biol Toxicol 2018; 35:111-127. [DOI: 10.1007/s10565-018-9437-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Accepted: 06/21/2018] [Indexed: 12/13/2022]
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47
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Gravina AG, Dallio M, Masarone M, Rosato V, Aglitti A, Persico M, Loguercio C, Federico A. Vascular Endothelial Dysfunction in Inflammatory Bowel Diseases: Pharmacological and Nonpharmacological Targets. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:2568569. [PMID: 29849875 PMCID: PMC5925080 DOI: 10.1155/2018/2568569] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Accepted: 03/14/2018] [Indexed: 12/19/2022]
Abstract
Inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, are chronic inflammatory conditions involving primarily the gastrointestinal tract. However, they may be also associated with systemic manifestations and comorbidities. The relationship between chronic inflammation and endothelial dysfunction has been extensively demonstrated. Mucosal immunity and gastrointestinal physiology are modified in inflammatory bowel diseases, and these modifications are mainly sustained by alterations of endothelial function. The key elements involved in this process are cytokines, inflammatory cells, growth factors, nitric oxide, endothelial adhesion molecules, and coagulation cascade factors. In this review, we discuss available data in literature concerning endothelial dysfunction in patients affected by inflammatory bowel disease and we focus our attention on both pharmacological and nonpharmacological therapeutic targets.
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Affiliation(s)
- Antonietta Gerarda Gravina
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via Pansini 5, 80131 Naples, Italy
| | - Marcello Dallio
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via Pansini 5, 80131 Naples, Italy
| | - Mario Masarone
- Department of Medicine and Surgery, University of Salerno, Via Salvador Allende, 84081 Baronissi, Salerno, Italy
| | - Valerio Rosato
- Department of Medicine and Surgery, University of Salerno, Via Salvador Allende, 84081 Baronissi, Salerno, Italy
| | - Andrea Aglitti
- Department of Medicine and Surgery, University of Salerno, Via Salvador Allende, 84081 Baronissi, Salerno, Italy
| | - Marcello Persico
- Department of Medicine and Surgery, University of Salerno, Via Salvador Allende, 84081 Baronissi, Salerno, Italy
| | - Carmelina Loguercio
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via Pansini 5, 80131 Naples, Italy
| | - Alessandro Federico
- Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Via Pansini 5, 80131 Naples, Italy
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Münzel T. Editorial commentary: The air that I breathe……………..makes me sick! Trends Cardiovasc Med 2018; 28:127-129. [DOI: 10.1016/j.tcm.2017.08.014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Accepted: 08/19/2017] [Indexed: 11/30/2022]
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Wada M, Takeshima T, Nakamura Y, Nagasaka S, Kamesaki T, Kajii E, Kotani K. Association between smoking and the peripheral vestibular disorder: a retrospective cohort study. Sci Rep 2017; 7:16889. [PMID: 29203808 PMCID: PMC5715055 DOI: 10.1038/s41598-017-17294-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 11/23/2017] [Indexed: 02/06/2023] Open
Abstract
Common inner ear diseases include peripheral vestibular disorder (PVD) and hearing impairment. The association between smoking and peripheral vestibular disorder (PVD) is unclear. We examined associations between smoking and new PVD events. In this retrospective study, we consecutively enrolled 393 participants aged ≥20 years [mean age 65.3 years; males 133 (33.8%)] treated for hypertension, dyslipidaemia, or diabetes mellitus at a primary care clinic between November 2011 and March 2013. Participants were categorized as ever-smokers (including current and past -smokers; divided per <30 and ≥30 pack-years), and never-smokers. New PVD events were reported over a 1-year follow-up period. Hazard ratios (HR) for new onset PVD were estimated using the Cox proportional hazard regression model. Compared to never-smokers, the adjusted HR was 2.22 for ever-smokers and 2.70 for all ever-smokers with ≥30 pack-years among all 393 participants. Among male participants, compared to never-smokers, the adjusted HR was 4.41 for ever-smokers with ≥30 pack-years. A smoking history of ≥30 pack-years was strongly associated with the risk of new onset PVD in males but not, females. This study may assist patients with smoking cessation for the prevention of new PVD events among males.
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Affiliation(s)
- Masaoki Wada
- Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan. .,Oki Clinic, Yuki, Japan.
| | - Taro Takeshima
- Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Yosikazu Nakamura
- Department of Public Health, Jichi Medical University, Shimotsuke, Japan
| | - Shoichiro Nagasaka
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Toyomi Kamesaki
- Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Eiji Kajii
- Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Kazuhiko Kotani
- Division of Community and Family Medicine, Center for Community Medicine, Jichi Medical University, Shimotsuke, Japan
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Niemann B, Rohrbach S, Miller MR, Newby DE, Fuster V, Kovacic JC. Oxidative Stress and Cardiovascular Risk: Obesity, Diabetes, Smoking, and Pollution: Part 3 of a 3-Part Series. J Am Coll Cardiol 2017; 70:230-251. [PMID: 28683970 DOI: 10.1016/j.jacc.2017.05.043] [Citation(s) in RCA: 225] [Impact Index Per Article: 28.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Revised: 04/25/2017] [Accepted: 05/10/2017] [Indexed: 12/16/2022]
Abstract
Oxidative stress occurs whenever the release of reactive oxygen species (ROS) exceeds endogenous antioxidant capacity. In this paper, we review the specific role of several cardiovascular risk factors in promoting oxidative stress: diabetes, obesity, smoking, and excessive pollution. Specifically, the risk of developing heart failure is higher in patients with diabetes or obesity, even with optimal medical treatment, and the increased release of ROS from cardiac mitochondria and other sources likely contributes to the development of cardiac dysfunction in this setting. Here, we explore the role of different ROS sources arising in obesity and diabetes, and the effect of excessive ROS production on the development of cardiac lipotoxicity. In parallel, contaminants in the air that we breathe pose a significant threat to human health. This paper provides an overview of cigarette smoke and urban air pollution, considering how their composition and biological effects have detrimental effects on cardiovascular health.
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Affiliation(s)
- Bernd Niemann
- Department of Adult and Pediatric Cardiovascular Surgery, University Hospital Giessen, Giessen, Germany
| | - Susanne Rohrbach
- Institute of Physiology, Justus-Liebig University, Giessen, Germany.
| | - Mark R Miller
- BHF/University of Edinburgh Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - David E Newby
- BHF/University of Edinburgh Centre for Cardiovascular Science, The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom.
| | - Valentin Fuster
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York; Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Icahn School of Medicine at Mount Sinai, New York, New York; Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain
| | - Jason C Kovacic
- The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York.
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