1
|
Ock J, Yin GN, Liu FY, Huang Y, Fridayana FR, Vo MN, Ryu JK. Ablation of IGFBP5 expression alleviates neurogenic erectile dysfunction by inducing neurovascular regeneration. Investig Clin Urol 2025; 66:74-86. [PMID: 39791587 PMCID: PMC11729225 DOI: 10.4111/icu.20240325] [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: 09/11/2024] [Revised: 11/08/2024] [Accepted: 11/17/2024] [Indexed: 01/12/2025] Open
Abstract
PURPOSE To investigate the therapeutic potential of eliminating insulin-like growth factor-binding protein 5 (IGFBP5) expression in improving erectile function in mice with cavernous nerve injury (CNI)-induced erectile dysfunction (ED). MATERIALS AND METHODS Eight-week-old male C57BL/6 mice were divided into four groups: a sham-operated group and three CNI-induced ED groups. The CNI-induced ED groups were treated with intracavernous injections 3 days before the CNI procedure. These injections included phosphate-buffered saline, scrambled control short hairpin RNA (shRNA), or shRNA targeting mouse IGFBP5 lentiviral particles. One week after CNI, erectile function was evaluated and the penile tissue was then harvested for histological examination and western blot analysis. Additionally, the major pelvic ganglia (MPG) and dorsal root ganglia (DRG) were cultured for ex vivo neurite outgrowth assays. RESULTS Following CNI, IGFBP5 expression in the cavernous tissues significantly increased, reaching its peak at day 7. First, ablation of IGFBP5 expression promotes neurite sprouting in MPG and DRG when exposed to lipopolysaccharide. Second, ablating IGFBP5 expression in CNI-induced ED mice improved erectile function, likely owing to increased neurovascular contents, including endothelial cells, pericytes, and neuronal processes. Third, ablating IGFBP5 expression in CNI-induced ED mice promoted neurovascular regeneration by increasing cell proliferation, reducing apoptosis, and decreasing Reactive oxygen species production. Finally, western blot analysis demonstrated that IGFBP5 ablation attenuated the JNK/c-Jun signaling pathway, activated the PI3K/AKT signaling pathway, and increased vascular endothelial growth factor and neurotrophic factor expression. CONCLUSIONS Ablating IGFBP5 expression enhanced neurovascular regeneration and ultimately improved erectile function in CNI-induced ED mice.
Collapse
Affiliation(s)
- Jiyeon Ock
- National Research Center for Sexual Medicine and Department of Urology, Inha University College of Medicine, Incheon, Korea
| | - Guo Nan Yin
- National Research Center for Sexual Medicine and Department of Urology, Inha University College of Medicine, Incheon, Korea
| | - Fang-Yuan Liu
- National Research Center for Sexual Medicine and Department of Urology, Inha University College of Medicine, Incheon, Korea
| | - Yan Huang
- National Research Center for Sexual Medicine and Department of Urology, Inha University College of Medicine, Incheon, Korea
- Program in Biomedical Science & Engineering, Inha University, Incheon, Korea
| | - Fitri Rahma Fridayana
- National Research Center for Sexual Medicine and Department of Urology, Inha University College of Medicine, Incheon, Korea
- Program in Biomedical Science & Engineering, Inha University, Incheon, Korea
| | - Minh Nhat Vo
- National Research Center for Sexual Medicine and Department of Urology, Inha University College of Medicine, Incheon, Korea
| | - Ji-Kan Ryu
- National Research Center for Sexual Medicine and Department of Urology, Inha University College of Medicine, Incheon, Korea
- Program in Biomedical Science & Engineering, Inha University, Incheon, Korea.
| |
Collapse
|
2
|
Roy R, Wilcox J, Webb AJ, O’Gallagher K. Dysfunctional and Dysregulated Nitric Oxide Synthases in Cardiovascular Disease: Mechanisms and Therapeutic Potential. Int J Mol Sci 2023; 24:15200. [PMID: 37894881 PMCID: PMC10607291 DOI: 10.3390/ijms242015200] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/11/2023] [Accepted: 10/13/2023] [Indexed: 10/29/2023] Open
Abstract
Nitric oxide (NO) plays an important and diverse signalling role in the cardiovascular system, contributing to the regulation of vascular tone, endothelial function, myocardial function, haemostasis, and thrombosis, amongst many other roles. NO is synthesised through the nitric oxide synthase (NOS)-dependent L-arginine-NO pathway, as well as the nitrate-nitrite-NO pathway. The three isoforms of NOS, namely neuronal (NOS1), inducible (NOS2), and endothelial (NOS3), have different localisation and functions in the human body, and are consequently thought to have differing pathophysiological roles. Furthermore, as we continue to develop a deepened understanding of the different roles of NOS isoforms in disease, the possibility of therapeutically modulating NOS activity has emerged. Indeed, impaired (or dysfunctional), as well as overactive (or dysregulated) NOS activity are attractive therapeutic targets in cardiovascular disease. This review aims to describe recent advances in elucidating the physiological role of NOS isoforms within the cardiovascular system, as well as mechanisms of dysfunctional and dysregulated NOS in cardiovascular disease. We then discuss the modulation of NO and NOS activity as a target in the development of novel cardiovascular therapeutics.
Collapse
Affiliation(s)
- Roman Roy
- Cardiovascular Department, King’s College Hospital NHS Foundation Trust, London SE5 9RS, UK;
| | - Joshua Wilcox
- Cardiovascular Department, Guy’s and St. Thomas’ NHS Foundation Trust, London SE1 7EH, UK;
| | - Andrew J. Webb
- Department of Clinical Pharmacology, British Heart Foundation Centre, School of Cardiovascular and Metabolic Medicine and Sciences, King’s College London, London SE1 7EH, UK;
| | - Kevin O’Gallagher
- Cardiovascular Department, King’s College Hospital NHS Foundation Trust, London SE5 9RS, UK;
- British Heart Foundation Centre of Research Excellence, School of Cardiovascular and Metabolic Medicine & Sciences, Faculty of Life Sciences & Medicine, King’s College London, London SE5 9NU, UK
| |
Collapse
|
3
|
Nakashima M, Nakamura K, Nishihara T, Ichikawa K, Nakayama R, Takaya Y, Toh N, Akagi S, Miyoshi T, Akagi T, Ito H. Association between Cardiovascular Disease and Liver Disease, from a Clinically Pragmatic Perspective as a Cardiologist. Nutrients 2023; 15:nu15030748. [PMID: 36771454 PMCID: PMC9919281 DOI: 10.3390/nu15030748] [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: 01/17/2023] [Revised: 01/28/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
Cardiovascular diseases and liver diseases are closely related. Non-alcoholic fatty liver disease has the same risk factors as those for atherosclerotic cardiovascular disease and may also be a risk factor for atherosclerotic cardiovascular disease on its own. Heart failure causes liver fibrosis, and liver fibrosis results in worsened cardiac preload and congestion. Although some previous reports regard the association between cardiovascular diseases and liver disease, the management strategy for liver disease in patients with cardiovascular diseases is not still established. This review summarized the association between cardiovascular diseases and liver disease. In patients with non-alcoholic fatty liver disease, the degree of liver fibrosis progresses with worsening cardiovascular prognosis. In patients with heart failure, liver fibrosis could be a prognostic marker. Liver stiffness assessed with shear wave elastography, the fibrosis-4 index, and non-alcoholic fatty liver disease fibrosis score is associated with both liver fibrosis in patients with liver diseases and worse prognosis in patients with heart failure. With the current population ageing, the importance of management for cardiovascular diseases and liver disease has been increasing. However, whether management and interventions for liver disease improve the prognosis of cardiovascular diseases has not been fully understood. Future investigations are needed.
Collapse
|
4
|
Luteolin improves vasoconstriction function and survival of septic mice via AMPK/NF-κB pathway. Heliyon 2023; 9:e13330. [PMID: 36816271 PMCID: PMC9932738 DOI: 10.1016/j.heliyon.2023.e13330] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 12/19/2022] [Accepted: 01/26/2023] [Indexed: 02/01/2023] Open
Abstract
Septic shock, the leading cause of death in sepsis, is related to vasoconstriction dysfunction. To investigate the effects of Luteolin (LTL), a flavonoid polyphenol compound, on vasoconstriction dysfunction in septic mice and the underlying mechanism, cecal ligation and puncture (CLP) surgery was performed on wild-type C57BL/6 mice to induce septic shock. Mice were intraperitoneally injected with 0.2 mg/kg LTL within 10 min after CLP surgery with or without 20 mg/kg Compound C (AMPK inhibitor) (CC) 1 h before CLP surgery, and re-administrated every 12 h. The survival rate, systolic arterial pressure (SAP), diastolic arterial pressure (DAP), and mean arterial pressure (MAP) were explored. After the mice were sacrificed, the vasoconstriction function, inflammatory indicators, and possible regulatory signaling pathways were examined. Our data showed that CLP decreased the survival rate, SAP, DAP, MAP, vasoconstriction function, and expression of ADRA1A and p-AMPK/AMPK, as well as increased the mRNA expression of inflammatory cytokines and iNOS, the serum levels of inflammatory cytokines, and the levels of iNOS, p-p65/p65, and p-IκBα/IκBα in aortas (P < 0.05), which could be reversed by LTL treatment (P < 0.05). However, inhibition of AMPK could abolish the protective effects of LTL (P < 0.05). In conclusion, our study manifested that LTL could prevent vasoconstriction dysfunction and increase survival of septic mice via activating AMPK, which suggested that LTL could be a novel therapeutic option for patients with sepsis.
Collapse
|
5
|
Zhang L, Li C, Wang S, Avtanski D, Hadzi-Petrushev N, Mitrokhin V, Mladenov M, Wang F. Tetrahydrocurcumin-Related Vascular Protection: An Overview of the Findings from Animal Disease Models. Molecules 2022; 27:5100. [PMID: 36014335 PMCID: PMC9412611 DOI: 10.3390/molecules27165100] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 08/01/2022] [Accepted: 08/05/2022] [Indexed: 01/05/2023] Open
Abstract
Tetrahydrocurcumin (THC), one of the major metabolites of CUR, possesses several CUR-like pharmacological effects; however, its mechanisms of action are largely unknown. This manuscript aims to summarize the literature on the preventive role of THC on vascular dysfunction and the development of hypertension by exploring the effects of THC on hemodynamic status, aortic elasticity, and oxidative stress in vasculature in different animal models. We review the protective effects of THC against hypertension induced by heavy metals (cadmium and iron), as well as its impact on arterial stiffness and vascular remodeling. The effects of THC on angiogenesis in CaSki xenografted mice and the expression of vascular endothelial growth factor (VEGF) are well documented. On the other hand, as an anti-inflammatory and antioxidant compound, THC is involved in enhancing homocysteine-induced mitochondrial remodeling in brain endothelial cells. The experimental evidence regarding the mechanism of mitochondrial dysfunction during cerebral ischemic/reperfusion injury and the therapeutic potential of THC to alleviate mitochondrial cerebral dysmorphic dysfunction patterns is also scrutinized and explored. Overall, the studies on different animal models of disease suggest that THC can be used as a dietary supplement to protect against cardiovascular changes caused by various factors (such as heavy metal overload, oxidative stress, and carcinogenesis). Additionally, the reviewed literature data seem to confirm THC's potential to improve mitochondrial dysfunction in cerebral vasculature during ischemic stroke through epigenetic mechanisms. We suggest that further preclinical studies should be implemented to demonstrate THC's vascular-protective, antiangiogenic, and anti-tumorigenic effects in humans. Applying the methods used in the presently reviewed studies would be useful and will help define the doses and methods of THC administration in various disease settings.
Collapse
Affiliation(s)
- Li Zhang
- Cancer Center, Department of Medical Oncology, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China
| | - Changhu Li
- Cancer Center, Division of Radiation Physics, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Sicheng Wang
- Medical Department, 6th City Clinical Hospital, 220037 Minsk, Belarus
| | - Dimiter Avtanski
- Friedman Diabetes Institute, Lenox Hill Hospital, Northwell Health, 110 E 59th Street, New York, NY 10022, USA
| | - Nikola Hadzi-Petrushev
- Faculty of Natural Sciences and Mathematics, Institute of Biology, “Ss. Cyril and Methodius” University, P.O. Box 162, 1000 Skopje, North Macedonia
| | - Vadim Mitrokhin
- Department of Physiology, Pirogov Russian National Research Medical University, Ostrovityanova Street, 1, 117997 Moscow, Russia
| | - Mitko Mladenov
- Faculty of Natural Sciences and Mathematics, Institute of Biology, “Ss. Cyril and Methodius” University, P.O. Box 162, 1000 Skopje, North Macedonia
- Department of Physiology, Pirogov Russian National Research Medical University, Ostrovityanova Street, 1, 117997 Moscow, Russia
| | - Feng Wang
- Cancer Center, Department of Medical Oncology, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China
| |
Collapse
|
6
|
White Wine—Induced Endothelium-Dependent Vasorelaxation in Sprague-Dawley Rats. Antioxidants (Basel) 2022; 11:antiox11050944. [PMID: 35624811 PMCID: PMC9137674 DOI: 10.3390/antiox11050944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/06/2022] [Accepted: 05/09/2022] [Indexed: 11/16/2022] Open
Abstract
The vasodilatory activity and polyphenolic content of commercially available white wine is low compared to red wines. This study assessed the vasodilator potential of white wines produced by four different fermentation processes: (1) white wine produced by the standard procedure; (2) grapes left to macerate completely for 30 days; (3) grapes left to macerate up to half of unfermented sugar; and (4) wine produced by cooling the must. All tested wine samples were analyzed for their phenolic content, antioxidant capacity, and ethanol content. Vasodilation was examined in the norepinephrine pre-contracted isolated rat aortas of male Sprague-Dawley rats randomly exposed to cumulative concentrations (0.1‰ to 8‰ final dilutions in organ baths) of each of the tested wine samples with or without quercetin and/or gallic acid supplementation, in the absence/presence of NOS inhibitor L-NAME. Standard procedure and the procedure involving must cooling gives wine with lower phenolic content, antioxidant capacity, and lower vasodilator potential, respectively. L-NAME inhibited vasodilation to all wine samples. Quercetin with or without gallic acid supplementation restored vasodilation. Results show that vasodilation to white wine is NO-dependent and suggest the possibility of increasing the antioxidant capacity and vasodilatory potential of white wine using different production procedures, depending on quercetin content.
Collapse
|
7
|
Ogresta D, Mrzljak A, Cigrovski Berkovic M, Bilic-Curcic I, Stojsavljevic-Shapeski S, Virovic-Jukic L. Coagulation and Endothelial Dysfunction Associated with NAFLD: Current Status and Therapeutic Implications. J Clin Transl Hepatol 2022; 10:339-355. [PMID: 35528987 PMCID: PMC9039716 DOI: 10.14218/jcth.2021.00268] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 09/24/2021] [Accepted: 10/08/2021] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is closely related to insulin resistance, type 2 diabetes mellitus and obesity. It is considered a multisystem disease and there is a strong association with cardiovascular disease and arterial hypertension, which interfere with changes in the coagulation system. Coagulation disorders are common in patients with hepatic impairment and are dependent on the degree of liver damage. Through a review of the literature, we consider and discuss possible disorders in the coagulation cascade and fibrinolysis, endothelial dysfunction and platelet abnormalities in patients with NAFLD.
Collapse
Affiliation(s)
- Doris Ogresta
- Department of Gastroenterology and Hepatology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
| | - Anna Mrzljak
- Department of Gastroenterology and Hepatology, University Hospital Center Zagreb, Zagreb, Croatia
- Department of Medicine, University of Zagreb, School of Medicine, Zagreb, Croatia
| | - Maja Cigrovski Berkovic
- Department for Endocrinology, Diabetes and Pharmacology, University Hospital Dubrava, Zagreb, Croatia
- Department of Kinesiological Anthropology and Methodology, Faculty of Kinesiology, University of Zagreb
- Department of Pharmacology, Faculty of Medicine, University of JJ Strossmayer, Osijek, Croatia
| | - Ines Bilic-Curcic
- Department of Pharmacology, Faculty of Medicine, University of JJ Strossmayer, Osijek, Croatia
- Department of Diabetes, Endocrinology and Metabolism Disorders, University Hospital Osijek, Osijek, Croatia
| | | | - Lucija Virovic-Jukic
- Department of Gastroenterology and Hepatology, Sestre Milosrdnice University Hospital Center, Zagreb, Croatia
- Department of Medicine, University of Zagreb, School of Medicine, Zagreb, Croatia
| |
Collapse
|
8
|
Aggarwal H, Pathak P, Singh V, Kumar Y, Shankar M, Das B, Jagavelu K, Dikshit M. Vancomycin-Induced Modulation of Gram-Positive Gut Bacteria and Metabolites Remediates Insulin Resistance in iNOS Knockout Mice. Front Cell Infect Microbiol 2022; 11:795333. [PMID: 35127558 PMCID: PMC8807491 DOI: 10.3389/fcimb.2021.795333] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2021] [Accepted: 12/23/2021] [Indexed: 12/27/2022] Open
Abstract
The role of oxidative and nitrosative stress has been implied in both physiology and pathophysiology of metabolic disorders. Inducible nitric oxide synthase (iNOS) has emerged as a crucial regulator of host metabolism and gut microbiota activity. The present study examines the role of the gut microbiome in determining host metabolic functions in the absence of iNOS. Insulin-resistant and dyslipidemic iNOS-/- mice displayed reduced microbial diversity, with a higher relative abundance of Allobaculum and Bifidobacterium, gram-positive bacteria, and altered serum metabolites along with metabolic dysregulation. Vancomycin, which largely depletes gram-positive bacteria, reversed the insulin resistance (IR), dyslipidemia, and related metabolic anomalies in iNOS-/- mice. Such improvements in metabolic markers were accompanied by alterations in the expression of genes involved in fatty acid synthesis in the liver and adipose tissue, lipid uptake in adipose tissue, and lipid efflux in the liver and intestine tissue. The rescue of IR in vancomycin-treated iNOS-/- mice was accompanied with the changes in select serum metabolites such as 10-hydroxydecanoate, indole-3-ethanol, allantoin, hippurate, sebacic acid, aminoadipate, and ophthalmate, along with improvement in phosphatidylethanolamine to phosphatidylcholine (PE/PC) ratio. In the present study, we demonstrate that vancomycin-mediated depletion of gram-positive bacteria in iNOS-/- mice reversed the metabolic perturbations, dyslipidemia, and insulin resistance.
Collapse
Affiliation(s)
- Hobby Aggarwal
- Pharmacology Division, Council of Scientific and Industrial Research (CSIR)-Central Drug Research Institute, Lucknow, India
| | - Priya Pathak
- Pharmacology Division, Council of Scientific and Industrial Research (CSIR)-Central Drug Research Institute, Lucknow, India
| | - Vishal Singh
- Department of Nutritional Sciences, The Pennsylvania State University, State College, PA, United States
| | - Yashwant Kumar
- Non-Communicable Diseases Division, Translational Health Science and Technology Institute, Faridabad, India
| | - Manoharan Shankar
- Microbial Physiology Laboratory, Department of Bioscience & Bioengineering, Indian Institute of Technology, Jodhpur, India
| | - Bhabatosh Das
- Molecular Genetics Laboratory, Infection and Immunology Division, Translational Health Science and Technology Institute, Faridabad, India
| | - Kumaravelu Jagavelu
- Pharmacology Division, Council of Scientific and Industrial Research (CSIR)-Central Drug Research Institute, Lucknow, India
| | - Madhu Dikshit
- Pharmacology Division, Council of Scientific and Industrial Research (CSIR)-Central Drug Research Institute, Lucknow, India
- Non-Communicable Diseases Division, Translational Health Science and Technology Institute, Faridabad, India
| |
Collapse
|
9
|
Soda K. Overview of Polyamines as Nutrients for Human Healthy Long Life and Effect of Increased Polyamine Intake on DNA Methylation. Cells 2022; 11:cells11010164. [PMID: 35011727 PMCID: PMC8750749 DOI: 10.3390/cells11010164] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/24/2021] [Accepted: 12/28/2021] [Indexed: 02/04/2023] Open
Abstract
Polyamines, spermidine and spermine, are synthesized in every living cell and are therefore contained in foods, especially in those that are thought to contribute to health and longevity. They have many physiological activities similar to those of antioxidant and anti-inflammatory substances such as polyphenols. These include antioxidant and anti-inflammatory properties, cell and gene protection, and autophagy activation. We have first reported that increased polyamine intake (spermidine much more so than spermine) over a long period increased blood spermine levels and inhibited aging-associated pathologies and pro-inflammatory status in humans and mice and extended life span of mice. However, it is unlikely that the life-extending effect of polyamines is exerted by the same bioactivity as polyphenols because most studies using polyphenols and antioxidants have failed to demonstrate their life-extending effects. Recent investigations revealed that aging-associated pathologies and lifespan are closely associated with DNA methylation, a regulatory mechanism of gene expression. There is a close relationship between polyamine metabolism and DNA methylation. We have shown that the changes in polyamine metabolism affect the concentrations of substances and enzyme activities involved in DNA methylation. I consider that the increased capability of regulation of DNA methylation by spermine is a key of healthy long life of humans.
Collapse
Affiliation(s)
- Kuniyasu Soda
- Department Cardiovascular Institute for Medical Research, Saitama Medical Center, Jichi Medical University, 1-847, Amanuma, Saitama-City 330-0834, Saitama, Japan
| |
Collapse
|
10
|
Queiroz RF, Stanley CP, Wolhuter K, Kong SMY, Rajivan R, McKinnon N, Nguyen GTH, Roveri A, Guttzeit S, Eaton P, Donald WA, Ursini F, Winterbourn CC, Ayer A, Stocker R. Hydrogen peroxide signaling via its transformation to a stereospecific alkyl hydroperoxide that escapes reductive inactivation. Nat Commun 2021; 12:6626. [PMID: 34785665 PMCID: PMC8595612 DOI: 10.1038/s41467-021-26991-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 10/28/2021] [Indexed: 11/16/2022] Open
Abstract
During systemic inflammation, indoleamine 2,3-dioxygenase 1 (IDO1) becomes expressed in endothelial cells where it uses hydrogen peroxide (H2O2) to oxidize L-tryptophan to the tricyclic hydroperoxide, cis-WOOH, that then relaxes arteries via oxidation of protein kinase G 1α. Here we show that arterial glutathione peroxidases and peroxiredoxins that rapidly eliminate H2O2, have little impact on relaxation of IDO1-expressing arteries, and that purified IDO1 forms cis-WOOH in the presence of peroxiredoxin 2. cis-WOOH oxidizes protein thiols in a selective and stereospecific manner. Compared with its epimer trans-WOOH and H2O2, cis-WOOH reacts slower with the major arterial forms of glutathione peroxidases and peroxiredoxins while it reacts more readily with its target, protein kinase G 1α. Our results indicate a paradigm of redox signaling by H2O2 via its enzymatic conversion to an amino acid-derived hydroperoxide that 'escapes' effective reductive inactivation to engage in selective oxidative activation of key target proteins.
Collapse
Affiliation(s)
- Raphael F Queiroz
- Department of Natural Sciences, Southwest Bahia State University, Vitoria da Conquista, Bahia, Brazil
- Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia
| | - Christopher P Stanley
- Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia
- Heart Research Institute, The University of Sydney, Sydney, Australia
| | - Kathryn Wolhuter
- Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia
| | | | - Ragul Rajivan
- Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia
| | - Naomi McKinnon
- Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia
| | - Giang T H Nguyen
- School of Chemistry, University of New South Wales, Sydney, New South Wales, Australia
| | - Antonella Roveri
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | | | - Philip Eaton
- William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK
| | - William A Donald
- School of Chemistry, University of New South Wales, Sydney, New South Wales, Australia
| | - Fulvio Ursini
- Department of Molecular Medicine, University of Padova, Padova, Italy
| | - Christine C Winterbourn
- Centre for Free Radical Research, Department of Pathology, University of Otago Christchurch, Christchurch, New Zealand
| | - Anita Ayer
- Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
- Heart Research Institute, The University of Sydney, Sydney, Australia.
- St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
| | - Roland Stocker
- Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
- Heart Research Institute, The University of Sydney, Sydney, Australia.
- St Vincent's Clinical School, University of New South Wales, Sydney, New South Wales, Australia.
- School of Life and Environmental Sciences, The University of Sydney, Sydney, Australia.
| |
Collapse
|
11
|
Yuan S, Hahn SA, Miller MP, Sanker S, Calderon MJ, Sullivan M, Dosunmu-Ogunbi AM, Fazzari M, Li Y, Reynolds M, Wood KC, St Croix CM, Stolz D, Cifuentes-Pagano E, Navas P, Shiva S, Schopfer FJ, Pagano PJ, Straub AC. Cooperation between CYB5R3 and NOX4 via coenzyme Q mitigates endothelial inflammation. Redox Biol 2021; 47:102166. [PMID: 34656824 PMCID: PMC8577475 DOI: 10.1016/j.redox.2021.102166] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Revised: 09/03/2021] [Accepted: 09/06/2021] [Indexed: 12/12/2022] Open
Abstract
NADPH oxidase 4 (NOX4) regulates endothelial inflammation by producing hydrogen peroxide (H2O2) and to a lesser extent O2•-. The ratio of NOX4-derived H2O2 and O2•- can be altered by coenzyme Q (CoQ) mimics. Therefore, we hypothesize that cytochrome b5 reductase 3 (CYB5R3), a CoQ reductase abundant in vascular endothelial cells, regulates inflammatory activation. To examine endothelial CYB5R3 in vivo, we created tamoxifen-inducible endothelium-specific Cyb5r3 knockout mice (R3 KO). Radiotelemetry measurements of systolic blood pressure showed systemic hypotension in lipopolysaccharides (LPS) challenged mice, which was exacerbated in R3 KO mice. Meanwhile, LPS treatment caused greater endothelial dysfunction in R3 KO mice, evaluated by acetylcholine-induced vasodilation in the isolated aorta, accompanied by elevated mRNA expression of vascular adhesion molecule 1 (Vcam-1). Similarly, in cultured human aortic endothelial cells (HAEC), LPS and tumor necrosis factor α (TNF-α) induced VCAM-1 protein expression was enhanced by Cyb5r3 siRNA, which was ablated by silencing the Nox4 gene simultaneously. Moreover, super-resolution confocal microscopy indicated mitochondrial co-localization of CYB5R3 and NOX4 in HAECs. APEX2-based electron microscopy and proximity biotinylation also demonstrated CYB5R3's localization on the mitochondrial outer membrane and its interaction with NOX4, which was further confirmed by the proximity ligation assay. Notably, Cyb5r3 knockdown HAECs showed less total H2O2 but more mitochondrial O2•-. Using inactive or non-membrane bound active CYB5R3, we found that CYB5R3 activity and membrane translocation are needed for optimal generation of H2O2 by NOX4. Lastly, cells lacking the CoQ synthesizing enzyme COQ6 showed decreased NOX4-derived H2O2, indicating a requirement for endogenous CoQ in NOX4 activity. In conclusion, CYB5R3 mitigates endothelial inflammatory activation by assisting in NOX4-dependent H2O2 generation via CoQ.
Collapse
Affiliation(s)
- Shuai Yuan
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Scott A Hahn
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Megan P Miller
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Subramaniam Sanker
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Michael J Calderon
- Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mara Sullivan
- Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA
| | - Atinuke M Dosunmu-Ogunbi
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Marco Fazzari
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Yao Li
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Michael Reynolds
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | - Katherine C Wood
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA
| | | | - Donna Stolz
- Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, PA, USA
| | - Eugenia Cifuentes-Pagano
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Placido Navas
- Centro Andaluz de Biología del Desarrollo and CIBERER, Instituto de Salud Carlos III, Universidad Pablo de Olavide-CSIC-JA, Sevilla, Spain, Spain
| | - Sruti Shiva
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Francisco J Schopfer
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA; Pittsburgh Liver Research Center (PLRC), University of Pittsburgh, Pittsburgh, PA, USA
| | - Patrick J Pagano
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Adam C Straub
- Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA, USA; Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA; Center for Microvascular Research, University of Pittsburgh, Pittsburgh, PA, USA.
| |
Collapse
|
12
|
Nüse B, Mattner J. L-arginine as a novel target for clinical intervention in inflammatory bowel disease. EXPLORATION OF IMMUNOLOGY 2021. [DOI: 10.37349/ei.2021.00008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/08/2021] [Indexed: 04/17/2025]
Abstract
Arginase-1 (Arg1) and the inducible nitric oxide synthase 2 (NOS2) compete for the common substrate L-arginine, semi-essential amino acid, and central intestinal metabolite. Both enzymes exhibit various, sometimes opposing effects on immune responses, tissue regeneration, or microbial growth and replication. In sub-mucosal tissues of patients suffering from inflammatory bowel disease (IBD), similar as in experimental colitis, the expression and activity of both enzymes, Arg1 and NOS2 are more prominent than in respective controls. Accordingly, the metabolism of L-arginine is altered in IBD patients. Thus, L-arginine represents a promising medical target for clinical intervention in these devastating diseases. Previous studies primarily focused on the host side of L-arginine metabolism. Initial reports using Arg1 inhibitors generated conflicting results in murine colitis models. Subsequently, only the generation of conditional Arg1 knockout mice allowed reliable functional analyses of Arg1 and the L-arginine metabolism in the immune system. Utilizing cell-specific conditional Arg1 knockouts, we have recently reported that Arg1, surprisingly, hampered the resolution of experimental colitis due to the restriction of the intraluminal availability of L-arginine. Reduced levels of L-arginine restrained the compositional diversity of the intestinal microbiota and subsequently the mutual metabolism between the microbiota and the host. Thus, the intraluminal microbiota represents a potential therapeutic target for L-arginine metabolism aside from host-dependent L-arginine consumption.
Collapse
Affiliation(s)
- Björn Nüse
- 1Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany
| | - Jochen Mattner
- Mikrobiologisches Institut-Klinische Mikrobiologie, Immunologie und Hygiene, Universitätsklinikum Erlangen, Friedrich-Alexander Universität (FAU) Erlangen-Nürnberg, 91054 Erlangen, Germany 2Medical Immunology Campus Erlangen, FAU Erlangen-Nürnberg, 91054 Erlangen, Germany
| |
Collapse
|
13
|
Wang XK, Peng ZG. Targeting Liver Sinusoidal Endothelial Cells: An Attractive Therapeutic Strategy to Control Inflammation in Nonalcoholic Fatty Liver Disease. Front Pharmacol 2021; 12:655557. [PMID: 33935770 PMCID: PMC8082362 DOI: 10.3389/fphar.2021.655557] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 03/10/2021] [Indexed: 12/12/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), especially its advanced stage nonalcoholic steatohepatitis (NASH), has become a threatened public health problem worldwide. However, no specific drug has been approved for clinical use to treat patients with NASH, though there are many promising candidates against NAFLD in the drug development pipeline. Recently, accumulated evidence showed that liver sinusoidal endothelial cells (LSECs) play an essential role in the occurrence and development of liver inflammation in patients with NAFLD. LSECs, as highly specialized endothelial cells with unique structure and anatomical location, contribute to the maintenance of liver homeostasis and could be a promising therapeutic target to control liver inflammation of NAFLD. In this review, we outline the pathophysiological roles of LSECs related to inflammation of NAFLD, highlight the pro-inflammatory and anti-inflammatory effects of LSECs, and discuss the potential drug development strategies against NAFLD based on targeting to LSECs.
Collapse
Affiliation(s)
- Xue-Kai Wang
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Zong-Gen Peng
- CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Key Laboratory of Biotechnology of Antibiotics, National Health and Family Planning Commission, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| |
Collapse
|
14
|
Lv D, Luo M, Yan J, Yang X, Luo S. Protective Effect of Sirtuin 3 on CLP-Induced Endothelial Dysfunction of Early Sepsis by Inhibiting NF-κB and NLRP3 Signaling Pathways. Inflammation 2021; 44:1782-1792. [PMID: 33770326 DOI: 10.1007/s10753-021-01454-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 03/15/2021] [Accepted: 03/18/2021] [Indexed: 01/07/2023]
Abstract
It has been revealed that widespread vascular endothelial dysfunction occurs in septic shock, ultimately resulting in multiple organ failure. The mitochondrial deacetylase sirtuin 3 (SIRT3) is essential in the regulation of metabolism, anti-inflammation, and anti-oxidation. The purpose of this study is to investigate whether SIRT3 is associated with the pathological progression of endothelial dysfunction in sepsis. Septic shock model was induced by cecal ligation and puncture (CLP) surgery on wild-type C57BL/6 mice. We activated and inhibited the function of SIRT3 with honokiol (HKL) and 3-TYP, respectively, and then biochemical, inflammatory, and endothelial function parameters of vascular tissue and survival were determined after CLP. CLP significantly activated NF-κB and NLRP3 pathways and decreased survival rate, endothelium-dependent relaxation function, and expression of Ser1177 phosphorylation of endothelial nitric oxide synthase (p-eNOS). The activation of SIRT3 significantly attenuated the increases of NF-κB and NLRP3 pathways and the declines of p-eNOS, endothelium-dependent relaxation function, and survival rate in septic mice. However, it presented exactly opposite results if SIRT3 was suppressed. We suggested that SIRT3 had a critical protective effect against vascular inflammation and endothelial dysfunction in early sepsis. Our data support a potential therapeutic target in vascular dysfunction and septic shock.
Collapse
Affiliation(s)
- Dingyi Lv
- Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Institute of Life Science, Chongqing Medical University, Chongqing, 400016, China
| | - Minghao Luo
- Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Institute of Life Science, Chongqing Medical University, Chongqing, 400016, China
| | - Jianghong Yan
- Institute of Life Science, Chongqing Medical University, Chongqing, 400016, China
| | - Xiyang Yang
- Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China
- Institute of Life Science, Chongqing Medical University, Chongqing, 400016, China
| | - Suxin Luo
- Department of Cardiology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
- Institute of Life Science, Chongqing Medical University, Chongqing, 400016, China.
- The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
| |
Collapse
|
15
|
Tubeimoside I improves survival of mice in sepsis by inhibiting inducible nitric oxide synthase expression. Biomed Pharmacother 2020; 126:110083. [DOI: 10.1016/j.biopha.2020.110083] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2020] [Revised: 03/05/2020] [Accepted: 03/05/2020] [Indexed: 12/12/2022] Open
|
16
|
Luo M, Meng J, Yan J, Shang F, Zhang T, Lv D, Li C, Yang X, Luo S. Role of the Nucleotide-Binding Domain-Like Receptor Protein 3 Inflammasome in the Endothelial Dysfunction of Early Sepsis. Inflammation 2020; 43:1561-1571. [DOI: 10.1007/s10753-020-01232-x] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
|
17
|
Small molecule inhibitors and stimulators of inducible nitric oxide synthase in cancer cells from natural origin (phytochemicals, marine compounds, antibiotics). Biochem Pharmacol 2020; 176:113792. [PMID: 31926145 DOI: 10.1016/j.bcp.2020.113792] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Accepted: 01/03/2020] [Indexed: 02/06/2023]
Abstract
Nitric oxide synthases (NOS) are a family of isoforms, which generate nitric oxide (NO). NO is one of the smallest molecules in nature and acts mainly as a potent vasodilator. It participates in various biological processes ranging from physiological to pathological conditions. Inducible NOS (iNOS, NOS2) is a calcium-independent and inducible isoform. Despite high iNOS expression in many tumors, the role of iNOS is still unclear and complex with both enhancing and prohibiting actions in tumorigenesis. Nature presents a broad variety of natural stimulators and inhibitors, which may either promote or inhibit iNOS response. In the present review, we give an overview of iNOS-modulating agents with a special focus on both natural and synthetic molecules and their effects in related biological processes. The role of iNOS in physiological and pathological conditions is also discussed.
Collapse
|
18
|
Ergocalciferol improves endothelial vasodilatory and vasoconstrictor function in an in vivo model of mild uraemia. Biosci Rep 2019; 39:221375. [PMID: 31789348 PMCID: PMC6923332 DOI: 10.1042/bsr20190711] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 11/20/2019] [Accepted: 11/21/2019] [Indexed: 01/21/2023] Open
Abstract
Endothelial dysfunction and vitamin D deficiency are prevalent in patients with cardiovascular disease (CVD) and chronic kidney disease (CKD). Both are risk factors for cardiovascular events in patients with CKD. No studies have investigated the effect of nutritional forms of vitamin D on endothelial function in earlier stages of CKD, when vascular endothelium may be more amenable to this therapy. We studied the effect of ergocalciferol in a pre-clinical model of mild uraemia. Male Wistar rats underwent either a 5/6th nephrectomy or sham surgery. Four weeks after the final stage of the surgery, these two groups were randomly allocated to placebo or an oral dose of 1000 iu of ergocalcfierol at day 7 and 2 pre sacrifice. Vascular responses to acetylcholine, Spermine NONOate and phenylephrine were determined in aortic rings. Blood pressure, calcium, phosphate and parathyroid hormone were measured in all groups. Ergocalciferol significantly improved the endothelium-dependent responses to acetylcholine and overcame the blunting of the contractile response to phenylephrine seen in uraemic animals. Ergocalciferol improved the contractile response to potassium chloride in uraemic, but not sham animals. All effects occurred independently of changes to calcium, phosphate, parathyroid hormone and systolic blood pressure. There were no differences in endothelium-independent relaxation to Spermine NONOate. In summary, in a model of mild uraemia, ergocalciferol improved vasodilator and vasoconstrictor tone independently of blood pressure and bone mineral parameters suggesting a direct effect of ergocalciferol on the endothelium.
Collapse
|
19
|
Vasoreactivity of isolated aortic rings from dyslipidemic and insulin resistant inducible nitric oxide synthase knockout mice. Eur J Pharmacol 2019; 855:90-97. [DOI: 10.1016/j.ejphar.2019.05.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Revised: 04/29/2019] [Accepted: 05/03/2019] [Indexed: 12/13/2022]
|
20
|
Hammoutene A, Rautou PE. Role of liver sinusoidal endothelial cells in non-alcoholic fatty liver disease. J Hepatol 2019; 70:1278-1291. [PMID: 30797053 DOI: 10.1016/j.jhep.2019.02.012] [Citation(s) in RCA: 222] [Impact Index Per Article: 37.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 02/10/2019] [Accepted: 02/13/2019] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) and its complications are an expanding health problem associated with the metabolic syndrome. Liver sinusoidal endothelial cells (LSECs) are highly specialized endothelial cells localized at the interface between the blood derived from the gut and the adipose tissue on the one side, and other liver cells on the other side. In physiological conditions, LSECs are gatekeepers of liver homeostasis. LSECs display anti-inflammatory and anti-fibrogenic properties by preventing Kupffer cell and hepatic stellate cell activation and regulating intrahepatic vascular resistance and portal pressure. This review focusses on changes occurring in LSECs in NAFLD and on their consequences on NAFLD progression and complications. Capillarization, namely the loss of LSEC fenestrae, and LSEC dysfunction, namely the loss of the ability of LSECs to generate vasodilator agents in response to increased shear stress both occur early in NAFLD. These LSEC changes favour steatosis development and set the stage for NAFLD progression. At the stage of non-alcoholic steatohepatitis, altered LSECs release inflammatory mediators and contribute to the recruitment of inflammatory cells, thus promoting liver injury and inflammation. Altered LSECs also fail to maintain hepatic stellate cell quiescence and release fibrogenic mediators, including Hedgehog signalling molecules, promoting liver fibrosis. Liver angiogenesis is increased in NAFLD and contributes to liver inflammation and fibrosis, but also to hepatocellular carcinoma development. Thus, improving LSEC health appears to be a promising approach to prevent NAFLD progression and complications.
Collapse
Affiliation(s)
- Adel Hammoutene
- Inserm, UMR-970, Paris Cardiovascular Research Center, PARCC, Paris, France; University Paris Descartes, Paris, France
| | - Pierre-Emmanuel Rautou
- Inserm, UMR-970, Paris Cardiovascular Research Center, PARCC, Paris, France; INSERM, UMR1149, Centre de Recherche sur l'Inflammation, Paris, France; University Paris Diderot, Paris, France; Service d'Hépatologie, Centre de Référence des Maladies Vasculaires du Foie, DHU Unity, Pôle des Maladies de l'Appareil Digestif, Hôpital Beaujon, AP-HP, Clichy, France.
| |
Collapse
|
21
|
Soda K. Polyamine Metabolism and Gene Methylation in Conjunction with One-Carbon Metabolism. Int J Mol Sci 2018; 19:E3106. [PMID: 30309036 PMCID: PMC6213949 DOI: 10.3390/ijms19103106] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Revised: 10/01/2018] [Accepted: 10/05/2018] [Indexed: 02/07/2023] Open
Abstract
Recent investigations have revealed that changes in DNA methylation status play an important role in aging-associated pathologies and lifespan. The methylation of DNA is regulated by DNA methyltransferases (DNMT1, DNMT3a, and DNMT3b) in the presence of S-adenosylmethionine (SAM), which serves as a methyl group donor. Increased availability of SAM enhances DNMT activity, while its metabolites, S-adenosyl-l-homocysteine (SAH) and decarboxylated S-adenosylmethionine (dcSAM), act to inhibit DNMT activity. SAH, which is converted from SAM by adding a methyl group to cytosine residues in DNA, is an intermediate precursor of homocysteine. dcSAM, converted from SAM by the enzymatic activity of adenosylmethionine decarboxylase, provides an aminopropyl group to synthesize the polyamines spermine and spermidine. Increased homocysteine levels are a significant risk factor for the development of a wide range of conditions, including cardiovascular diseases. However, successful homocysteine-lowering treatment by vitamins (B6, B12, and folate) failed to improve these conditions. Long-term increased polyamine intake elevated blood spermine levels and inhibited aging-associated pathologies in mice and humans. Spermine reversed changes (increased dcSAM, decreased DNMT activity, aberrant DNA methylation, and proinflammatory status) induced by the inhibition of ornithine decarboxylase. The relation between polyamine metabolism, one-carbon metabolism, DNA methylation, and the biological mechanism of spermine-induced lifespan extension is discussed.
Collapse
Affiliation(s)
- Kuniyasu Soda
- Cardiovascular Research Institute, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma, Omiya, Saitama-city, Saitama Prefecture 330-8503, Japan.
| |
Collapse
|
22
|
Meng J, Zhou C, Hu B, Luo M, Yang Y, Wang Y, Wang W, Jiang G, Hong J, Li S, Wu H, Yan S, Yan W. Stevioside Prevents Wear Particle-Induced Osteolysis by Inhibiting Osteoclastogenesis and Inflammatory Response via the Suppression of TAK1 Activation. Front Pharmacol 2018; 9:1053. [PMID: 30319406 PMCID: PMC6169369 DOI: 10.3389/fphar.2018.01053] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Accepted: 08/31/2018] [Indexed: 12/28/2022] Open
Abstract
Aseptic loosening and periprosthetic osteolysis are the leading causes of total joint arthroplasty failure, which occurs as a result of chronic inflammatory response and enhanced osteoclast activity. Here we showed that stevioside, a natural compound isolated from Stevia rebaudiana, exhibited preventative effects on titanium particle-induced osteolysis in a mouse calvarial model. Further histological assessment and real-time PCR analysis indicated that stevioside prevented titanium particle-induced osteolysis by inhibiting osteoclast formation and inflammatory cytokine expression in vivo. In vitro, we found that stevioside could suppress RANKL-induced osteoclastogenesis and titanium particle-induced inflammatory response in a dose-dependent manner. Mechanistically, stevioside achieved these effects by disrupting the phosphorylation of TAK1 and subsequent activation of NF-κB/MAPKs signaling pathways. Collectively, our data suggest that stevioside effectively suppresses osteoclastogenesis and inflammatory response both in vitro and in vivo, and it might be a potential therapy for particle-induced osteolysis and other osteolytic diseases.
Collapse
Affiliation(s)
- Jiahong Meng
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Orthopedic Research Institute of Zhejiang University, Hangzhou, China
| | - Chenhe Zhou
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Orthopedic Research Institute of Zhejiang University, Hangzhou, China
| | - Bin Hu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Orthopedic Research Institute of Zhejiang University, Hangzhou, China
| | - Mengmeng Luo
- Department of Plastic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yute Yang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Orthopedic Research Institute of Zhejiang University, Hangzhou, China
| | - Yangxin Wang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Orthopedic Research Institute of Zhejiang University, Hangzhou, China
| | - Wei Wang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Orthopedic Research Institute of Zhejiang University, Hangzhou, China
| | - Guangyao Jiang
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Orthopedic Research Institute of Zhejiang University, Hangzhou, China
| | - Jianqiao Hong
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Orthopedic Research Institute of Zhejiang University, Hangzhou, China
| | - Sihao Li
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Orthopedic Research Institute of Zhejiang University, Hangzhou, China
| | - Haobo Wu
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Orthopedic Research Institute of Zhejiang University, Hangzhou, China
| | - Shigui Yan
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Orthopedic Research Institute of Zhejiang University, Hangzhou, China
| | - Weiqi Yan
- Department of Orthopedic Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Orthopedic Research Institute of Zhejiang University, Hangzhou, China
| |
Collapse
|
23
|
Zöllner J, Howe LG, Edey LF, O'Dea KP, Takata M, Gordon F, Leiper J, Johnson MR. The response of the innate immune and cardiovascular systems to LPS in pregnant and nonpregnant mice. Biol Reprod 2018; 97:258-272. [PMID: 29044422 DOI: 10.1093/biolre/iox076] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2016] [Accepted: 07/13/2017] [Indexed: 11/14/2022] Open
Abstract
Sepsis is the leading cause of direct maternal mortality, but there are no data directly comparing the response to sepsis in pregnant and nonpregnant (NP) individuals. This study uses a mouse model of sepsis to test the hypothesis that the cardiovascular response to sepsis is more marked during pregnancy. Female CD1 mice had radiotelemetry probes implanted and were time mated. NP and day 16 pregnant CD-1 mice received intraperitoneal lipopolysaccharide (LPS; 10 μg, serotype 0111: B4). In a separate study, tissue and serum (for RNA, protein and flow cytometry studies), aorta and uterine vessels (for wire myography) were collected after LPS or vehicle control administration. Administration of LPS resulted in a greater fall in blood pressure in pregnant mice compared to NP mice. This occurred with similar changes in the circulating levels of cytokines, vasoactive factors, and circulating leukocytes, but with a greater monocyte and lesser neutrophil margination in the lungs of pregnant mice. Baseline markers of cardiac dysfunction and apoptosis as well as cytokine expression were higher in pregnant mice, but the response to LPS was similar in both groups as was the ex vivo assessment of vascular function. In pregnant mice, nonfatal sepsis is associated with a more marked hypotensive response but not a greater immune response. We conclude that endotoxemia induces a more marked hypotensive response in pregnant compared to NP mice. These changes were not associated with a more marked systemic inflammatory response in pregnant mice, although monocyte lung margination was greater. The more marked hypotensive response to LPS may explain the greater vulnerability to some infections exhibited by pregnant women.
Collapse
Affiliation(s)
- Julia Zöllner
- Imperial College Parturition Research Group, Chelsea and Westminster Hospital, 369 Fulham Road, London, UK.,Imperial College Parturition Research Group, Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus DuCane Road, London, UK.,MRC Clinical Sciences Centre, Hammersmith Hospital Campus, DuCane Road, London, UK
| | - Laura G Howe
- Imperial College Parturition Research Group, Chelsea and Westminster Hospital, 369 Fulham Road, London, UK.,Imperial College Parturition Research Group, Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus DuCane Road, London, UK.,MRC Clinical Sciences Centre, Hammersmith Hospital Campus, DuCane Road, London, UK
| | - Lydia F Edey
- Imperial College Parturition Research Group, Chelsea and Westminster Hospital, 369 Fulham Road, London, UK.,Imperial College Parturition Research Group, Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus DuCane Road, London, UK
| | - Kieran P O'Dea
- Section of Anaesthetics, Pain Medicine, and Intensive Care, Faculty of Medicine, Chelsea and Westminster Hospital, London, UK
| | - Masao Takata
- Section of Anaesthetics, Pain Medicine, and Intensive Care, Faculty of Medicine, Chelsea and Westminster Hospital, London, UK
| | - Fabiana Gordon
- Statistical Advisory Service, School Of Public Health, UG15, Ground Floor (Mezzanine), Medical School, St Mary's Campus, Norfolk Place, London, UK
| | - James Leiper
- MRC Clinical Sciences Centre, Hammersmith Hospital Campus, DuCane Road, London, UK
| | - Mark R Johnson
- Imperial College Parturition Research Group, Chelsea and Westminster Hospital, 369 Fulham Road, London, UK.,Imperial College Parturition Research Group, Institute of Reproductive and Developmental Biology, Hammersmith Hospital Campus DuCane Road, London, UK
| |
Collapse
|
24
|
Nor Arfuzir NN, Agarwal R, Iezhitsa I, Agarwal P, Sidek S, Spasov A, Ozerov A, Mohd Ismail N. Effect of Magnesium Acetyltaurate and Taurine on Endothelin1-Induced Retinal Nitrosative Stress in Rats. Curr Eye Res 2018; 43:1032-1040. [PMID: 29676937 DOI: 10.1080/02713683.2018.1467933] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
PURPOSE Retinal ganglion cell apoptosis in glaucoma is associated with elevated levels of endothelin-1 (ET1), a potent vasoconstrictor. ET1-induced retinal ischemia leads to altered expression of nitric oxide synthase (NOS) isoforms leading to increased formation of nitric oxide (NO) and retinal nitrosative stress. Since magnesium (Mg) is known to improve endothelial functions and reduce oxidative stress and taurine (TAU) possesses potent antioxidant properties, we investigated the protective effects of magnesium acetyltaurate (MgAT) against ET1-induced nitrosative stress and retinal damage in rats. We also compared the effects of MgAT with that of TAU alone. METHODS Sprague Dawley rats were intravitreally injected with ET1. MgAT and TAU were administered as pre-, co-, or posttreatment. Subsequently, the expression of NOS isoforms was detected in retina by immunohistochemistry, retinal nitrotyrosine level was estimated using ELISA, and retinal cell apoptosis was detected by TUNEL staining. RESULTS Intravitreal ET1 caused a significant increase in the expressions of nNOS and iNOS while eNOS expression was significantly reduced compared to vehicle treated group. Administration of both MgAT and TAU restored the altered levels of NOS isoform expression, reduced retinal nitrosative stress and retinal cell apoptosis. The effect of MgAT, however, was greater than that of TAU alone. CONCLUSIONS MgAT and TAU prevent ET1-induced retinal cell apoptosis by reducing retinal nitrosative stress in Sprague Dawley rats. Addition of TAU to Mg seems to enhance the efficacy of TAU compared to when given alone. Moreover, the pretreatment with MgAT/TAU showed higher efficacy compared to co- or posttreatment.
Collapse
Affiliation(s)
- Natasha Najwa Nor Arfuzir
- a Center for Neuroscience Research, Faculty of Medicine , Universiti Teknologi MARA Sungai Buloh Campus , Selangor , Malaysia
| | - Renu Agarwal
- a Center for Neuroscience Research, Faculty of Medicine , Universiti Teknologi MARA Sungai Buloh Campus , Selangor , Malaysia
| | - Igor Iezhitsa
- a Center for Neuroscience Research, Faculty of Medicine , Universiti Teknologi MARA Sungai Buloh Campus , Selangor , Malaysia.,b Volgograd State Medical University, Research Institute of Pharmacology , Volgograd , Russia
| | - Puneet Agarwal
- c Faculty of Medicine, International Medical University , IMU Clinical School , Seremban , Malaysia
| | - Sabrilhakim Sidek
- a Center for Neuroscience Research, Faculty of Medicine , Universiti Teknologi MARA Sungai Buloh Campus , Selangor , Malaysia
| | - Alexander Spasov
- b Volgograd State Medical University, Research Institute of Pharmacology , Volgograd , Russia
| | - Alexander Ozerov
- b Volgograd State Medical University, Research Institute of Pharmacology , Volgograd , Russia
| | - Nafeeza Mohd Ismail
- a Center for Neuroscience Research, Faculty of Medicine , Universiti Teknologi MARA Sungai Buloh Campus , Selangor , Malaysia
| |
Collapse
|
25
|
Abstract
PURPOSE OF REVIEW Sepsis is a common and frequently fatal condition in which mortality has been consistently linked to increasing organ dysfunction. For example, acute kidney injury (AKI) occurs in 40-50% of septic patients and increases mortality six to eight-fold. However, the mechanisms by which sepsis causes organ dysfunction are not well understood and hence current therapy remains reactive and nonspecific. RECENT FINDINGS Recent studies have challenged the previous notion that organ dysfunction is solely secondary to hypoperfusion, by showing, for example, that AKI occurs in the setting of normal or increased renal blood flow; and that it is characterized not by acute tubular necrosis or apoptosis, but rather by heterogeneous areas of colocalized sluggish peritubular blood flow and tubular epithelial cell oxidative stress. Evidence has also shown that microvascular dysfunction, inflammation, and the metabolic response to inflammatory injury are fundamental pathophysiologic mechanisms that may explain the development of sepsis-induced AKI. SUMMARY The implications of these findings are significant because in the context of decades of negative clinical trials in the field, the recognition that other mechanisms are at play opens the possibility to better understand the processes of injury and repair, and provides an invaluable opportunity to design mechanism-targeted therapeutic interventions.
Collapse
|
26
|
Falconer D, Papageorgiou N, Salem K, Lim WY, Katsargyris A, Avgerinos E, Tousoulis D. Nitric oxide donors for peripheral artery disease. Curr Opin Pharmacol 2018; 39:77-85. [PMID: 29587164 DOI: 10.1016/j.coph.2018.02.009] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2017] [Revised: 02/18/2018] [Accepted: 02/22/2018] [Indexed: 01/02/2023]
Abstract
Current management of peripheral arterial disease involves risk factor modification and revascularisation, but many patients are still left with debilitating symptoms. Therefore, new treatment strategies are needed. The importance of nitric oxide, and its role in regulating endothelial function, is well-established. Altering the nitric oxide pathway has been extensively studied as a means of treating vascular disease, including peripheral arterial disease. Statins and ACE inhibitors have been shown to enhance endogenous nitric oxide and improve intermittent claudication symptoms. Studies using l-arginine have produced differing results, for reasons for yet fully understood. A greater understanding of the nitric oxide pathway, and its enzymatic control, has generated more potential therapeutic targets to alter NO levels.
Collapse
Affiliation(s)
| | | | - Karim Salem
- Division of Vascular Surgery, University of Pittsburgh Medical Center, Pittsburgh, USA
| | - Wei Yao Lim
- Barts Heart Centre, St Bartholomew's Hospital, London, UK
| | - Athanasios Katsargyris
- Department of Vascular and Endovascular Surgery, Paracelsus Medical University, Nuremberg, Germany
| | - Efthimios Avgerinos
- Division of Vascular Surgery, University of Pittsburgh Medical Center, Pittsburgh, USA
| | - Dimitris Tousoulis
- 1st Cardiology Department, Athens University Medical School, Athens, Greece
| |
Collapse
|
27
|
Choy KW, Lau YS, Murugan D, Vanhoutte PM, Mustafa MR. Paeonol Attenuates LPS-Induced Endothelial Dysfunction and Apoptosis by Inhibiting BMP4 and TLR4 Signaling Simultaneously but Independently. J Pharmacol Exp Ther 2018; 364:420-432. [PMID: 29259041 DOI: 10.1124/jpet.117.245217] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2017] [Accepted: 12/14/2017] [Indexed: 03/08/2025] Open
Abstract
Inflammatory injury of the endothelium leads to apoptosis and endothelial dysfunction. The current study explored the effect and mechanisms of paeonol in inflammation-induced apoptosis and endothelial dysfunction induced by lipopolysaccharides (LPSs). The effects of paeonol on LPS-induced inflammatory injury were assessed by Western blotting, flow cytometry and reactive oxygen species (ROS) measurement in human umbilical vein endothelial cells (HUVECs) and C57BL/6J mice. Vascular reactivity of isolated mouse aortae was examined using wire myographs. The exposure of HUVECs to LPS increased the protein presence of Toll-like receptor 4 (TLR4), bone morphogenic protein 4 (BMP4), BMP receptor type 1A, nicotinamide adenine dinucleotide phosphate oxidase subunit 2, mitogen-activated protein kinase (MAPK), inducible nitric oxide synthase (iNOS), and cleaved caspase 3, as well as decreased it in phosphorylated endothelial nitric oxide synthase; these effects were prevented by treatment with paeonol. Similarly, cotreatment with paeonol reversed BMP4-induced apoptosis in HUVECs. Relaxation in response to the endothelium-dependent vasodilator acetylcholine were impaired in mouse aortae after exposure to LPSs; this endothelial dysfunction was reversed by cotreatment with paeonol, noggin (a BMP4 inhibitor), TAK242 (TLR4 antagonist), apocynin (an ROS scavenger), MAPK inhibitors, and AG (an iNOS inhibitor). BMP4 small interfering RNAs (siRNAs) abolished LPS-induced upregulation of BMP4 and cleaved caspase 3 protein, but not in cells treated with TLR4 siRNA and vice versa. The silencing of TLR4 and BMP4 abolished the inhibitory effects of paeonol on LPS-induced activation of cleaved caspase 3. The present results demonstrate that paeonol reduces LPS-induced endothelial dysfunction and apoptosis by inhibiting TLR4 and BMP4 signaling independently.
Collapse
Affiliation(s)
- Ker Woon Choy
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia (K.W.C., Y.S.L., D.M., M.R.M.); and State Key Laboratory of Pharmaceutical Biotechnology, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China (P.M.V.)
| | - Yeh Siang Lau
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia (K.W.C., Y.S.L., D.M., M.R.M.); and State Key Laboratory of Pharmaceutical Biotechnology, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China (P.M.V.)
| | - Dharmani Murugan
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia (K.W.C., Y.S.L., D.M., M.R.M.); and State Key Laboratory of Pharmaceutical Biotechnology, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China (P.M.V.)
| | - Paul M Vanhoutte
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia (K.W.C., Y.S.L., D.M., M.R.M.); and State Key Laboratory of Pharmaceutical Biotechnology, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China (P.M.V.)
| | - Mohd Rais Mustafa
- Department of Pharmacology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia (K.W.C., Y.S.L., D.M., M.R.M.); and State Key Laboratory of Pharmaceutical Biotechnology, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China (P.M.V.)
| |
Collapse
|
28
|
Pasarín M, Abraldes JG, Liguori E, Kok B, La Mura V. Intrahepatic vascular changes in non-alcoholic fatty liver disease: Potential role of insulin-resistance and endothelial dysfunction. World J Gastroenterol 2017; 23:6777-6787. [PMID: 29085222 PMCID: PMC5645612 DOI: 10.3748/wjg.v23.i37.6777] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2017] [Revised: 08/31/2017] [Accepted: 09/20/2017] [Indexed: 02/06/2023] Open
Abstract
Metabolic syndrome is a cluster of several clinical conditions characterized by insulin-resistance and high cardiovascular risk. Non-alcoholic fatty liver disease is the liver expression of the metabolic syndrome, and insulin resistance can be a frequent comorbidity in several chronic liver diseases, in particular hepatitis C virus infection and/or cirrhosis. Several studies have demonstrated that insulin action is not only relevant for glucose control, but also for vascular homeostasis. Insulin regulates nitric oxide production, which mediates to a large degree the vasodilating, anti-inflammatory and antithrombotic properties of a healthy endothelium, guaranteeing organ perfusion. The effects of insulin on the liver microvasculature and the effects of IR on sinusoidal endothelial cells have been studied in animal models of non-alcoholic fatty liver disease. The hypotheses derived from these studies and the potential translation of these results into humans are critically discussed in this review.
Collapse
Affiliation(s)
- Marcos Pasarín
- Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, IDIBAPS (Institut d’Investigacions Biomèdiques August Pi i Sunyer), University of Barcelona, 08036 Barcelona, Spain
| | - Juan G Abraldes
- Cirrhosis Care Clinic, Division of Gastroenterology (Liver Unit), CEGIIR, University of Alberta, AB T6G 2R3 Edmonton, Canada
| | - Eleonora Liguori
- Internal Medicine, IRCCS San Donato, Department of Biomedical Sciences for Health, University of Milan, 20097 San Donato Milanese, Italy
| | - Beverley Kok
- Cirrhosis Care Clinic, Division of Gastroenterology (Liver Unit), CEGIIR, University of Alberta, AB T6G 2R3 Edmonton, Canada
| | - Vincenzo La Mura
- Internal Medicine, IRCCS San Donato, Department of Biomedical Sciences for Health, University of Milan, 20097 San Donato Milanese, Italy
| |
Collapse
|
29
|
Effects of SPAK on vascular reactivity and nitric oxide production in endotoxemic mice. Eur J Pharmacol 2017; 814:248-254. [PMID: 28864211 DOI: 10.1016/j.ejphar.2017.08.038] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 08/21/2017] [Accepted: 08/28/2017] [Indexed: 11/20/2022]
Abstract
Vasoplegia impedes therapeutic interventions to restore vascular tone, leading to severe hypotension, poor tissue perfusion, and multiple organ failure in septic shock. High levels of circulating nitric oxide (NO) play a crucial role in endotoxin-induced vascular hyporeactivity. Proinflammatory cytokines have been implicated in the induction of inducible NO synthase and overproduction of NO. Anti-inflammatory therapy can diminish NO formation and improve vascular hyporeactivity in septic shock. STE20/SPS1-realted proline/alanine-rich kinase (SPAK) has been reported to activate mitogen-activated protein kinase and contribute to intestinal inflammation. Thus, we evaluated the roles of SPAK in NO production and vascular hyporeactivity in endotoxemic animals. Male wild-type and SPAK deficiency mice were intraperitoneally administered vehicle or Escherichia coli lipopolysaccharide (LPS, 50mg/kg). The changes of systolic blood pressure and plasma nitrate and nitrite levels were measured during the experimental period. Thoracic aortas were exercised to assess vascular reactivity and SPAK expression. In the present study, mice in endotoxin model showed severe hypotension and hyporeactivity to serotonin, phenylephrine (PE), and acetylcholine in the aortic rings. Phosphorylated SPAK expression in the aorta and NO levels in the plasma were also increased in animals with endotoxic shock. However, deletion of SPAK not only reduced the elevation of NO levels but also improved vascular hyporeactivity to serotonin and PE in endotoxemic mice. Taken together, SPAK could be involved in the NO overproduction and vascular hyporesponsiveness to vasoconstrictors in endotoxic shock. Thus, inhibition of SPAK could be useful in the prevention of endotoxin-induced vascular hyporeactivity.
Collapse
|
30
|
Lind M, Hayes A, Caprnda M, Petrovic D, Rodrigo L, Kruzliak P, Zulli A. Inducible nitric oxide synthase: Good or bad? Biomed Pharmacother 2017. [PMID: 28651238 DOI: 10.1016/j.biopha.2017.06.036] [Citation(s) in RCA: 156] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Nitric oxide synthases (NOS) are a family of isoforms responsible for the synthesis of the potent dilator nitric oxide (NO). Expression of inducible NOS (iNOS) occurs in conditions of inflammation, and produces large amounts of NO. In pathological conditions iNOS is regarded as a harmful enzyme and is proposed to be a major contributor to diseases of the cardiovascular system such as atherosclerosis. In this review, we address the notion that iNOS is a detrimental enzyme in disease and discuss its potentially beneficial roles. Additionally, we describe other molecules associated with iNOS in diseases such as atherosclerosis, and current research on therapeutic inhibitors tested to reduced pathology associated with cardiovascular diseases (CVD).
Collapse
Affiliation(s)
- Maggie Lind
- Centre for Chronic Disease (CCD), College of Health & Biomedicine, Victoria University, Melbourne, Victoria, Australia
| | - Alan Hayes
- Centre for Chronic Disease (CCD), College of Health & Biomedicine, Victoria University, Melbourne, Victoria, Australia
| | - Martin Caprnda
- 1st Department of Internal Medicine, Faculty of Medicine, Comenius University and University Hospital, Bratislava, Slovakia
| | - Daniel Petrovic
- Institute of Histology and Embryology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Luis Rodrigo
- Faculty of Medicine, University of Oviedo, Central University Hospital of Asturias (HUCA), Oviedo, Spain
| | - Peter Kruzliak
- Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Czech Republic; 2nd Department of Surgery, Centre of Vascular Diseases, Faculty of Medicine, Masaryk University and St. Anne´s Faculty Hospital, Brno, Czech Republic.
| | - Anthony Zulli
- Centre for Chronic Disease (CCD), College of Health & Biomedicine, Victoria University, Melbourne, Victoria, Australia.
| |
Collapse
|
31
|
Rocuronium Bromide Inhibits Inflammation and Pain by Suppressing Nitric Oxide Production and Enhancing Prostaglandin E 2 Synthesis in Endothelial Cells. Int Neurourol J 2016; 20:296-303. [PMID: 28043117 PMCID: PMC5209582 DOI: 10.5213/inj.1632796.398] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Accepted: 12/12/2016] [Indexed: 01/21/2023] Open
Abstract
Purpose Rocuronium bromide is a nondepolarizing neuromuscular blocking drug and has been used as an adjunct for relaxation or paralysis of the skeletal muscles, facilitation of endotracheal intubation, and improving surgical conditions during general anesthesia. However, intravenous injection of rocuronium bromide induces injection pain or withdrawal movement. The exact mechanism of rocuronium bromide-induced injection pain or withdrawal movement is not yet understood. We investigated whether rocuronium bromide treatment is involved in the induction of inflammation and pain in vascular endothelial cells. Methods For this study, calf pulmonary artery endothelial (CPAE) cells were used, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, Western blot, nitric oxide detection, and prostaglandin E2 immunoassay were conducted. Results Rocuronium bromide treatment inhibited endothelial nitric oxide synthase and suppressed nitric oxide production in CPAE cells. Rocuronium bromide activated cyclooxygenase-2, inducible nitric oxide synthase and increased prostaglandin E2 synthesis in CPAE cells. Conclusions Rocuronium bromide induced inflammation and pain in CPAE cells. Suppressing nitric oxide production and enhancing prostaglandin E2 synthesis might be associated with rocuronium bromide-induced injection pain or withdrawal movement.
Collapse
|
32
|
Synergistic Effects of Danshen (Salvia Miltiorrhiza Radix et Rhizoma) and Sanqi (Notoginseng Radix et Rhizoma) Combination in Inhibiting Inflammation Mediators in RAW264.7 Cells. BIOMED RESEARCH INTERNATIONAL 2016; 2016:5758195. [PMID: 27830149 PMCID: PMC5088307 DOI: 10.1155/2016/5758195] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/17/2016] [Accepted: 09/21/2016] [Indexed: 11/17/2022]
Abstract
Aims. This study aims to investigate the possible synergistic interactions of the Danshen-Sanqi combination on vascular disease via their anti-inflammatory activities. Methods. Nine combination ratios of Danshen-Sanqi extracts were screened in the RAW264.7 cell line and their anti-inflammatory effects were examined in lipopolysaccharide- (LPS-) induced nitric oxide (NO), tumor necrosis factor (TNF), and monocyte chemoattractant protein-1 (MCP-1) generation pathways. The interaction between Danshen and Sanqi on each target was analysed using combination index (CI) and isobologram models. Additionally, the anti-inflammatory activities of key bioactive compounds from Danshen and Sanqi were tested using the same models. The compounds from each herb that exerted the most potent activity were combined to evaluate their possible synergistic/antagonistic interactions. Results. Danshen-Sanqi 8 : 2 was found to be the optimal ratio and exerted a synergistic effect in inhibiting NO, TNF, and MCP-1 when the concentrations were higher than 1.24, 1.89, and 2.17 mg/mL, respectively. Although dihydrotanshinone I (DT) and ginsenoside Rd (Rd) from Danshen and Sanqi, respectively, exhibited the greatest individual bioactivity in the assays, antagonistic effects were observed for the DT-Rd combination 7 : 3. Conclusion. This study provided scientific evidence to support the traditional use of the Danshen-Sanqi combination for vascular disease through their synergistic interactions on anti-inflammatory pathways.
Collapse
|
33
|
Chuaiphichai S, Starr A, Nandi M, Channon KM, McNeill E. Endothelial cell tetrahydrobiopterin deficiency attenuates LPS-induced vascular dysfunction and hypotension. Vascul Pharmacol 2016; 77:69-79. [PMID: 26276526 PMCID: PMC4746318 DOI: 10.1016/j.vph.2015.08.009] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 07/16/2015] [Accepted: 08/10/2015] [Indexed: 11/21/2022]
Abstract
Overproduction of nitric oxide (NO) is thought to be a key mediator of the vascular dysfunction and severe hypotension in patients with endotoxaemia and septic shock. The contribution of NO produced directly in the vasculature by endothelial cells to the hypotension seen in these conditions, vs. the broader systemic increase in NO, is unclear. To determine the specific role of endothelium derived NO in lipopolysaccharide (LPS)-induced vascular dysfunction we administered LPS to mice deficient in endothelial cell tetrahydrobiopterin (BH4), the essential co-factor for NO production by NOS enzymes. Mice deficient in endothelial BH4 production, through loss of the essential biosynthesis enzyme Gch1 (Gch1(fl/fl)Tie2cre mice) received a 24hour challenge with LPS or saline control. In vivo LPS treatment increased vascular GTP cyclohydrolase and BH4 levels in aortas, lungs and hearts, but this increase was significantly attenuated in Gch1(fl/fl)Tie2cre mice, which were also partially protected from the LPS-induced hypotension. In isometric tension studies, in vivo LPS treatment reduced the vasoconstriction response and impaired endothelium-dependent and independent vasodilatations in mesenteric arteries from wild-type mice, but not in Gch1(fl/fl)Tie2cre mesenteric arteries. Ex vivo LPS treatment decreased vasoconstriction response to phenylephrine in aortic rings from wild-type and not in Gch1(fl/fl)Tie2cre mice, even in the context of significant eNOS and iNOS upregulation. These data provide direct evidence that endothelial cell NO has a significant contribution to LPS-induced vascular dysfunction and hypotension and may provide a novel therapeutic target for the treatment of systemic inflammation and patients with septic shock.
Collapse
Affiliation(s)
- Surawee Chuaiphichai
- British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, UK
| | - Anna Starr
- Pharmacology and Therapeutics Group, Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, UK
| | - Manasi Nandi
- Pharmacology and Therapeutics Group, Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, UK
| | - Keith M Channon
- British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, UK
| | - Eileen McNeill
- British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, UK; Wellcome Trust Centre for Human Genetics, University of Oxford, UK; Pharmacology and Therapeutics Group, Institute of Pharmaceutical Science, Faculty of Life Sciences & Medicine, King's College London, UK.
| |
Collapse
|
34
|
Umbro I, Gentile G, Tinti F, Muiesan P, Mitterhofer AP. Recent advances in pathophysiology and biomarkers of sepsis-induced acute kidney injury. J Infect 2015; 72:131-42. [PMID: 26702738 DOI: 10.1016/j.jinf.2015.11.008] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Revised: 11/24/2015] [Accepted: 11/28/2015] [Indexed: 12/26/2022]
Abstract
Sepsis is a complex clinical syndrome characterized by a systemic inflammatory response to an infective insult. This process often leads to widespread tissue injury and multiple organ dysfunction. In particular, the development of acute kidney injury (AKI) is one of the most frequent complications, which increases the complexity and cost of care, and is an independent risk factor for mortality. Previous suggestions highlighting systemic hypotension, renal vasoconstriction and ischaemia-reperfusion injury as the primary pathophysiological mechanisms involved in sepsis-induced AKI have been challenged. Recently it has been shown that sepsis-induced AKI occurs in the setting of microvascular dysfunction with release of microparticles, inflammation and energetic adaptation of highly metabolic organs to cellular stress. The intolerable high mortality rate associated with sepsis-induced AKI is partially explained by an incomplete understanding of its pathophysiology and a delay in diagnosis. The aim of this review is to focus on advances in understanding the sepsis pathophysiology, with particular attention to the fundamental mechanisms of sepsis-induced AKI and the potential diagnostic and prognostic markers involved.
Collapse
Affiliation(s)
- Ilaria Umbro
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Edgbaston, B15 2GW Birmingham, United Kingdom; Department of Clinical Medicine, Nephrology and Dialysis B, Sapienza University of Rome, Viale dell'Università 37, 00185 Rome, Italy.
| | - Giuseppe Gentile
- Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Via Benevento 6, 00185 Rome, Italy.
| | - Francesca Tinti
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Edgbaston, B15 2GW Birmingham, United Kingdom; Department of Clinical Medicine, Nephrology and Dialysis B, Sapienza University of Rome, Viale dell'Università 37, 00185 Rome, Italy.
| | - Paolo Muiesan
- The Liver Unit, Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Edgbaston, B15 2GW Birmingham, United Kingdom.
| | - Anna Paola Mitterhofer
- Department of Clinical Medicine, Nephrology and Dialysis B, Sapienza University of Rome, Viale dell'Università 37, 00185 Rome, Italy.
| |
Collapse
|
35
|
Recent knowledge on the pathophysiology of septic acute kidney injury: A narrative review. J Crit Care 2015; 31:82-9. [PMID: 26475099 DOI: 10.1016/j.jcrc.2015.09.017] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Revised: 09/13/2015] [Accepted: 09/13/2015] [Indexed: 01/03/2023]
Abstract
Sepsis is the commonest cause of acute kidney injury in critically ill patients. Its pathophysiology is complex and not well understood. Until recently, it was believed that kidney hypoperfusion is the major contributor of septic acute kidney injury. However, recent publications have improved our understanding on this topic. We now know that its mechanisms included the following: (1) renal macrocirculatory and microcirculatory disturbance, (2) surge of inflammatory markers and oxidative stress, (3) coagulation cascade activation, and (4) bioenergetics adaptive response with controlled cell-cycle arrest aiming to prevent cell death. Uncovering these complicated mechanisms may facilitate the development of more appropriate therapeutic measures in the future.
Collapse
|
36
|
Choudhury S, Kannan K, Pule Addison M, Darzi SA, Singh V, Singh TU, Thangamalai R, Dash JR, Parida S, Debroy B, Paul A, Mishra SK. Combined treatment with atorvastatin and imipenem improves survival and vascular functions in mouse model of sepsis. Vascul Pharmacol 2015; 71:139-50. [PMID: 25869507 DOI: 10.1016/j.vph.2015.03.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2014] [Revised: 02/28/2015] [Accepted: 03/03/2015] [Indexed: 01/22/2023]
Abstract
We have recently reported that pre-treatment, but not the post-treatment with atorvastatin showed survival benefit and improved hemodynamic functions in cecal ligation and puncture (CLP) model of sepsis in mice. Here we examined whether combined treatment with atorvastatin and imipenem after onset of sepsis can prolong survival and improve vascular functions. At 6 and 18h after sepsis induction, treatment with atorvastatin plus imipenem, atorvastatin or imipenem alone or placebo was initiated. Ex vivo experiments were done on mouse aorta to examine the vascular reactivity to nor-adrenaline and acetylcholine and mRNA expressions of α1D AR, GRK2 and eNOS. Atorvastatin plus imipenem extended the survival time to 56.00±4.62h from 20.00±1.66h observed in CLP mice. The survival time with atorvastatin or imipenem alone was 20.50±1.89h and 27.00±4.09h, respectively. The combined treatment reversed the hyporeactivity to nor-adrenaline through preservation of α1D AR mRNA/protein expression and reversal of α1D AR desensitization mediated by GRK2/Gβγ pathway. The treatment also restored endothelium-dependent relaxation to ACh through restoration of aortic eNOS mRNA expression and NO availability. In conclusion, combined treatment with atorvastatin and imipenem exhibited survival benefit and improved vascular functions in septic mice.
Collapse
Affiliation(s)
- Soumen Choudhury
- Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India
| | - Kandasamy Kannan
- Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India
| | - M Pule Addison
- Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India
| | - Sazad A Darzi
- Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India
| | - Vishakha Singh
- Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India
| | - Thakur Uttam Singh
- Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India
| | - Ramasamy Thangamalai
- Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India
| | - Jeevan Ranjan Dash
- Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India
| | - Subhashree Parida
- Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India
| | - Biplab Debroy
- Division of Veterinary Pathology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India
| | - Avishek Paul
- Division of Physiology and Climatology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India
| | - Santosh Kumar Mishra
- Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar-243122, Bareilly, Uttar Pradesh, India.
| |
Collapse
|
37
|
|
38
|
Kharitonova M, Iezhitsa I, Zheltova A, Ozerov A, Spasov A, Skalny A. Comparative angioprotective effects of magnesium compounds. J Trace Elem Med Biol 2015; 29:227-34. [PMID: 25127069 DOI: 10.1016/j.jtemb.2014.06.026] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2013] [Revised: 06/30/2014] [Accepted: 06/30/2014] [Indexed: 01/10/2023]
Abstract
Magnesium (Mg) deficiency is implicated in the development of numerous disorders of the cardiovascular system. Moreover, the data regarding the efficacy of different magnesium compounds in the correction of impaired functions due to low magnesium intake are often fragmentary and inconsistent. The aim of this study was to compare the effects of the most bioavailable Mg compounds (Mg l-aspartate, Mg N-acetyltaurate, Mg chloride, Mg sulphate and Mg oxybutyrate) on systemic inflammation and endothelial dysfunction in rats fed a low Mg diet for 74 days. A low Mg diet decreased the Mg concentration in the plasma and erythrocytes, which was accompanied by a reduced concentration of eNOs and increased levels of endothelin-1 level in the serum and impaired endothelium-dependent vasodilatation. These effects increased the concentration of proinflammatory molecules, such as VCAM-1, TNF-α, IL-6 and CRP, indicating the development of systemic inflammation and endothelial dysfunction. The increased total NO level, which estimated from the sum of the nitrate and nitrite concentrations in the serum, may also be considered to be a proinflammatory marker. Two weeks of Mg supplementation partially or fully normalised the ability of the vascular wall to effect adequate endothelium-dependent vasodilatation and reversed the levels of most endothelial dysfunction and inflammatory markers (except CRP) to the mean values of the control group. Mg sulphate had the smallest effect on the endothelin-1, TNF-α and VCAM-1 levels. Mg N-acetyltaurate was significantly more effective in restoring the level of eNOS compared to all other studied compounds, except for Mg oxybutyrate. Taken together, the present findings demonstrate that all Mg compounds equally alleviate endothelial dysfunction and inflammation caused by Mg deficiency. Mg sulphate tended to be the least effective compound.
Collapse
Affiliation(s)
- Maria Kharitonova
- Department of Pharmacology, Volgograd State Medical University, Pl. Pavshih Bortsov, 1, Volgograd 400131, Russia; Institute of Pharmacy, Department of Pharmacology and Toxicology, University of Innsbruck, Center for Chemistry and Biomedicine, Innrain 80-82/III, A-6020 Innsbruck, Austria
| | - Igor Iezhitsa
- Department of Pharmacology, Volgograd State Medical University, Pl. Pavshih Bortsov, 1, Volgograd 400131, Russia; Universiti Teknologi MARA, Faculty of Medicine, Sungai Buloh Campus, Jalan Hospital, 47000 Sungai Buloh, Selangor Darul Ehsan, Malaysia; Universiti Teknologi MARA (UiTM), RIG "Molecular Pharmacology and Advanced Therapeutics", Brain and Neuroscience Communities of Research, 40450 Shah Alam, Selangor Darul Ehsan, Malaysia.
| | - Anastasia Zheltova
- Department of Pharmacology, Volgograd State Medical University, Pl. Pavshih Bortsov, 1, Volgograd 400131, Russia; Department of Allergology and Immunology, Volgograd State Medical University, Pl. Pavshih Bortsov, 1, Volgograd 400131, Russia
| | - Alexander Ozerov
- Department for Pharmaceutical and Toxicological Chemistry, Volgograd State Medical University, Pl. Pavshih Bortsov, 1, Volgograd 400131, Russia
| | - Alexander Spasov
- Department of Pharmacology, Volgograd State Medical University, Pl. Pavshih Bortsov, 1, Volgograd 400131, Russia
| | - Anatoly Skalny
- Russian Society of Trace Elements in Medicine, 46 Zemlyanoy Val str., Moscow 105064, Russia; Trace Element - Institute for UNESCO, 7 rue Guillaume Paradin, 69008 Lyon, France
| |
Collapse
|
39
|
Sangartit W, Kukongviriyapan U, Donpunha W, Pakdeechote P, Kukongviriyapan V, Surawattanawan P, Greenwald SE. Tetrahydrocurcumin protects against cadmium-induced hypertension, raised arterial stiffness and vascular remodeling in mice. PLoS One 2014; 9:e114908. [PMID: 25502771 PMCID: PMC4263715 DOI: 10.1371/journal.pone.0114908] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Accepted: 11/14/2014] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Cadmium (Cd) is a nonessential heavy metal, causing oxidative damage to various tissues and associated with hypertension. Tetrahydrocurcumin (THU), a major metabolite of curcumin, has been demonstrated to be an antioxidant, anti-diabetic, anti-hypertensive and anti-inflammatory agent. In this study, we investigated the protective effect of THU against Cd-induced hypertension, raised arterial stiffness and vascular remodeling in mice. METHODS Male ICR mice received CdCl2 (100 mg/l) via drinking water for 8 weeks. THU was administered intragastrically at dose of 50 or 100 mg/kg/day concurrently with Cd treatment. RESULTS Administration of CdCl2 significantly increased arterial blood pressure, blunted vascular responses to vasoactive agents, increased aortic stiffness, and induced hypertrophic aortic wall remodeling by increasing number of smooth muscle cells and collagen deposition, decreasing elastin, and increasing matrix metalloproteinase (MMP)-2 and MMP-9 levels in the aortic medial wall. Supplementation with THU significantly decreased blood pressure, improved vascular responsiveness, and reversed the structural and mechanical alterations of the aortas, including collagen and elastin deposition. The reduction on the adverse response of Cd treatment was associated with upregulated eNOS and downregulated iNOS protein expressions, increased nitrate/nitrite level, alleviated oxidative stress and enhanced antioxidant glutathione. Moreover, THU also reduced the accumulation of Cd in the blood and tissues. CONCLUSIONS Our results suggest that THU ameliorates cadmium-induced hypertension, vascular dysfunction, and arterial stiffness in mice through enhancing NO bioavailability, attenuating oxidative stress, improving vascular remodeling and decreasing Cd accumulation in other tissues. THU has a beneficial effect in moderating the vascular alterations associated with Cd exposure.
Collapse
Affiliation(s)
- Weerapon Sangartit
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Upa Kukongviriyapan
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Wanida Donpunha
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Poungrat Pakdeechote
- Department of Physiology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Veerapol Kukongviriyapan
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Praphassorn Surawattanawan
- Research and Development Institute, The Government Pharmaceutical Organization, Rama VI Road, Ratchathewi, Bangkok 10400, Thailand
| | - Stephen E. Greenwald
- Pathology Group, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 1BB, United Kingdom
| |
Collapse
|
40
|
La Mura V, Pasarín M, Rodriguez-Vilarrupla A, García-Pagán JC, Bosch J, Abraldes JG. Liver sinusoidal endothelial dysfunction after LPS administration: a role for inducible-nitric oxide synthase. J Hepatol 2014; 61:1321-1327. [PMID: 25038487 DOI: 10.1016/j.jhep.2014.07.014] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2014] [Revised: 07/04/2014] [Accepted: 07/04/2014] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Sepsis is associated with microvascular dysfunction, which contributes to organ failure. Intrahepatic endothelial dysfunction occurs after exposure to lipopolysaccharide (LPS). The upregulation of inducible nitric oxide synthase (iNOS) has been shown to contribute to systemic vascular dysfunction after LPS administration. However, little is known about the effects of iNOS induction on the liver microcirculation. This study aimed at exploring, in the isolated rat liver perfusion model, the role of iNOS induction in liver microvascular dysfunction associated with endotoxemia. METHODS All experiments were conducted in male Wistar rats, after 24 h of LPS (5 mg/kg i.p.) or saline administration in the presence or absence of the iNOS inhibitor 1400 W (3 mg/kg i.p.), administered 3 and 23 h after LPS/saline injection. Liver microvascular function was assessed by isolated liver perfusion, followed by molecular studies and liver function tests. RESULTS At 24 h, LPS induced liver endothelial dysfunction, as shown by a decreased vasodilatory response to acetylcholine and decreased eNOS phosphorylation at Ser(1176). This was associated with liver injury, assessed by an increase in liver transaminases and decreased indocyanin green clearance, and increased nitrooxidative stress. iNOS inhibition prevented liver endothelial dysfunction, blunted the development of liver injury and attenuated LPS-induced nitrooxidative stress. CONCLUSIONS iNOS upregulation contributes to liver microvascular dysfunction in endotoxemia. This suggests that this mechanism deserves further exploration in studies addressing liver protection in the context of severe acute bacterial infection.
Collapse
Affiliation(s)
- Vincenzo La Mura
- Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS, University of Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Spain; Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico, Università di Milano, Milano, Italy
| | - Marcos Pasarín
- Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS, University of Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Spain
| | - Aina Rodriguez-Vilarrupla
- Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS, University of Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Spain
| | - Juan Carlos García-Pagán
- Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS, University of Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Spain
| | - Jaime Bosch
- Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS, University of Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Spain
| | - Juan G Abraldes
- Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clínic-IDIBAPS, University of Barcelona, and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Spain; Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Canada.
| |
Collapse
|
41
|
Starr A, Sand CA, Heikal L, Kelly PD, Spina D, Crabtree M, Channon KM, Leiper JM, Nandi M. Overexpression of GTP cyclohydrolase 1 feedback regulatory protein is protective in a murine model of septic shock. Shock 2014; 42:432-9. [PMID: 25046538 PMCID: PMC4851220 DOI: 10.1097/shk.0000000000000235] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 07/10/2014] [Indexed: 11/26/2022]
Abstract
Overproduction of nitric oxide (NO) by inducible NO synthase contributes toward refractory hypotension, impaired microvascular perfusion, and end-organ damage in septic shock patients. Tetrahydrobiopterin (BH4) is an essential NOS cofactor. GTP cyclohydrolase 1 (GCH1) is the rate-limiting enzyme for BH4 biosynthesis. Under inflammatory conditions, GCH1 activity and hence BH4 levels are increased, supporting pathological NOS activity. GCH1 activity can be controlled through allosteric interactions with GCH1 feedback regulatory protein (GFRP). We investigated whether overexpression of GFRP can regulate BH4 and NO production and attenuate cardiovascular dysfunction in sepsis. Sepsis was induced in mice conditionally overexpressing GFRP and wild-type littermates by cecal ligation and puncture. Blood pressure was monitored by radiotelemetry, and mesenteric blood flow was quantified by laser speckle contrast imaging. Blood biochemistry data were obtained using an iSTAT analyzer, and BH4 levels were measured in plasma and tissues by high-performance liquid chromatography. Increased BH4 and NO production and hypotension were observed in all mice, but the extents of these pathophysiological changes were attenuated in GFRP OE mice. Perturbations in blood biochemistry were similarly attenuated in GFRP OE compared with wild-type controls. These results suggest that GFRP overexpression regulates GCH1 activity during septic shock, which in turn limits BH4 bioavailability for iNOS. We conclude that the GCH1-GFRP axis is a critical regulator of BH4 and NO production and the cardiovascular derangements that occur in septic shock.
Collapse
Affiliation(s)
- Anna Starr
- *Pharmacology and Therapeutics Group, Institute of Pharmaceutical Science, School of Biomedical Sciences, King’s College London; and MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London; and British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Claire A. Sand
- *Pharmacology and Therapeutics Group, Institute of Pharmaceutical Science, School of Biomedical Sciences, King’s College London; and MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London; and British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Lamia Heikal
- *Pharmacology and Therapeutics Group, Institute of Pharmaceutical Science, School of Biomedical Sciences, King’s College London; and MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London; and British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Peter D. Kelly
- *Pharmacology and Therapeutics Group, Institute of Pharmaceutical Science, School of Biomedical Sciences, King’s College London; and MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London; and British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Domenico Spina
- *Pharmacology and Therapeutics Group, Institute of Pharmaceutical Science, School of Biomedical Sciences, King’s College London; and MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London; and British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Mark Crabtree
- *Pharmacology and Therapeutics Group, Institute of Pharmaceutical Science, School of Biomedical Sciences, King’s College London; and MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London; and British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Keith M. Channon
- *Pharmacology and Therapeutics Group, Institute of Pharmaceutical Science, School of Biomedical Sciences, King’s College London; and MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London; and British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - James M. Leiper
- *Pharmacology and Therapeutics Group, Institute of Pharmaceutical Science, School of Biomedical Sciences, King’s College London; and MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London; and British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| | - Manasi Nandi
- *Pharmacology and Therapeutics Group, Institute of Pharmaceutical Science, School of Biomedical Sciences, King’s College London; and MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London; and British Heart Foundation Centre of Research Excellence, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom
| |
Collapse
|
42
|
Goodwin JE, Feng Y, Velazquez H, Zhou H, Sessa WC. Loss of the endothelial glucocorticoid receptor prevents the therapeutic protection afforded by dexamethasone after LPS. PLoS One 2014; 9:e108126. [PMID: 25299055 PMCID: PMC4191990 DOI: 10.1371/journal.pone.0108126] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2014] [Accepted: 08/25/2014] [Indexed: 12/26/2022] Open
Abstract
Glucocorticoids are normally regarded as anti-inflammatory therapy for a wide variety of conditions and have been used with some success in treating sepsis and sepsis-like syndromes. We previously demonstrated that mice lacking the glucocorticoid receptor in the endothelium (GR EC KO mice) are extremely sensitive to low-dose LPS and demonstrate prolonged activation and up regulation of NF-κB. In this study we pre-treated these GR EC KO mice with dexamethasone and assessed their response to an identical dose of LPS. Surprisingly, the GR EC KO mice fared even worse than when given LPS alone demonstrating increased mortality, increased levels of the inflammatory cytokines TNF-α and IL-6 and increased nitric oxide release after the dexamethasone pre-treatment. As expected, control animals pre-treated with dexamethasone showed improvement in all parameters assayed. Mechanistically we demonstrate that GR EC KO mice show increased iNOS production and NF-κB activation despite treatment with dexamethasone.
Collapse
Affiliation(s)
- Julie E. Goodwin
- Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, United States of America
- * E-mail:
| | - Yan Feng
- Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - Heino Velazquez
- Department of Internal Medicine, Veterans Affairs Hospital, West Haven, Connecticut, United States of America
| | - Han Zhou
- Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, United States of America
| | - William C. Sessa
- Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, Connecticut, United States of America
- Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut, United States of America
| |
Collapse
|
43
|
Martin G, Asensi V, Montes AH, Collazos J, Alvarez V, Pérez-Is L, Carton JA, Taboada F, Valle-Garay E. Endothelial (NOS3 E298D) and inducible (NOS2 exon 22) nitric oxide synthase polymorphisms, as well as plasma NOx, influence sepsis development. Nitric Oxide 2014; 42:79-86. [PMID: 25239655 DOI: 10.1016/j.niox.2014.09.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2014] [Revised: 07/24/2014] [Accepted: 09/12/2014] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Nitric oxide (NO) influences susceptibility to infection and hemodynamic failure (HF) in sepsis. NOS3 and NOS2 SNPs might modify plasma nitrite/nitrate (NOx) levels, sepsis development, hemodynamics and survival. METHODS 90 severely septic and 91 non-infected ICU patients were prospectively studied. NOS3 (E298D), NOS3 (-786 T/C), NOS3 (27 bp-VNTR), and NOS2A (exon 22) SNPs and plasma NOx levels were assessed. RESULTS 21 patients (11.6%) died, 7 with sepsis. TT homozygotes and T allele carriers of NOS3 (E298D) and AG carriers of the NOS2A (exon 22) SNPs were more frequent among septic compared to non-infected ICU patients (p < 0.05). Plasma NOx was higher in septic, especially in septic with hemodynamic failure (HF) or fatal outcome (p < 0.006). Plasma NOx was higher in carriers of the T allele of the NOS3 (E298D) SNP (p = 0.006). Sepsis independently associated with HF, increased NOx, peripheral neutrophils, and fibrinogen levels, decreased prothrombin and the presence of the NOS3 (E298D) and NOS2A (exon 22) SNPs. A low APACHE II score was the only variable associated with sepsis survival. NOx was independently associated with sepsis, HF, decreased neutrophils and higher APACHE. CONCLUSIONS NOS3 (E298D) and NOS2A (exon 22) SNPs, individually and in combination, and plasma NOx, associated with sepsis development. NOx associated with HF and fatal outcome.
Collapse
Affiliation(s)
- Guadalupe Martin
- Critical Care, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
| | - Víctor Asensi
- Infectious Diseases Services, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain.
| | - A Hugo Montes
- Biochemistry and Molecular Biology, Oviedo University School of Medicine, Oviedo, Spain
| | - Julio Collazos
- Infectious Diseases Unit, Hospital de Galdácano, Vizcaya, Spain
| | - Victoria Alvarez
- Molecular Genetics Unit-Nephrology Research Institute, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
| | - Laura Pérez-Is
- Biochemistry and Molecular Biology, Oviedo University School of Medicine, Oviedo, Spain
| | - José A Carton
- Infectious Diseases Services, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
| | - Francisco Taboada
- Critical Care, Hospital Universitario Central de Asturias (HUCA), Oviedo, Spain
| | - Eulalia Valle-Garay
- Biochemistry and Molecular Biology, Oviedo University School of Medicine, Oviedo, Spain
| |
Collapse
|
44
|
A unified theory of sepsis-induced acute kidney injury: inflammation, microcirculatory dysfunction, bioenergetics, and the tubular cell adaptation to injury. Shock 2014; 41:3-11. [PMID: 24346647 DOI: 10.1097/shk.0000000000000052] [Citation(s) in RCA: 547] [Impact Index Per Article: 49.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Given that the leading clinical conditions associated with acute kidney injury (AKI), namely, sepsis, major surgery, heart failure, and hypovolemia, are all associated with shock, it is tempting to attribute all AKI to ischemia on the basis of macrohemodynamic changes. However, an increasing body of evidence has suggested that in many patients, AKI can occur in the absence of overt signs of global renal hypoperfusion. Indeed, sepsis-induced AKI can occur in the setting of normal or even increased renal blood flow. Accordingly, renal injury may not be entirely explained solely on the basis of the classic paradigm of hypoperfusion, and thus other mechanisms must come into play. Herein, we put forward a "unifying theory" to explain the interplay between inflammation and oxidative stress, microvascular dysfunction, and the adaptive response of the tubular epithelial cell to the septic insult. We propose that this response is mostly adaptive in origin, that it is driven by mitochondria, and that it ultimately results in and explains the clinical phenotype of sepsis-induced AKI.
Collapse
|
45
|
Soto ME, Soria-Castro E, Lans VG, Ontiveros EM, Mejía BIH, Hernandez HJM, García RB, Herrera V, Pérez-Torres I. Analysis of oxidative stress enzymes and structural and functional proteins on human aortic tissue from different aortopathies. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2014; 2014:760694. [PMID: 25101153 PMCID: PMC4102031 DOI: 10.1155/2014/760694] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Revised: 05/28/2014] [Accepted: 05/28/2014] [Indexed: 01/15/2023]
Abstract
The role of oxidative stress in different aortopathies is evaluated. Thirty-two tissue samples from 18 men and 14 women were divided into: 4 control (C) subjects, 11 patients with systemic arterial hypertension (SAH), 4 with variants of Marfan's syndrome (MV), 9 with Marfan's syndrome (M), 2 with Turner's syndrome, and 2 with Takayasu's arteritis (TA). Aorta fragments were homogenized. Lipoperoxidation (LPO), copper-zinc and manganese superoxide dismutase (Mn and Cu-Zn-SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione S-transferase (GST), endothelial nitric oxide synthase (eNOS), nitrates and nitrites (NO3(-)/NO2(-)), and type IV collagen, and laminin were evaluated. There was an increase in Mn- and Cu-Zn-SOD activity in SAH, MV, M, and Turner's syndrome. There was also an increase in CAT activity in M and Turner' syndrome. GPx and GST activity decreased and LPO increased in all groups. eNOS was decreased in SAH, MV, and M and NO3 (-)/NO2 (-) were increased in SAH and TA. Type IV collagen was decreased in Turner's syndrome and TA. Laminin γ-1 was decreased in MV and increased in M. In conclusion, similarities and differences in oxidative stress in the different aortopathies studied including pathologies with aneurysms were found with alterations in SOD, CAT, GPx, GST, and eNOS activity that modify subendothelial basement membrane proteins.
Collapse
Affiliation(s)
- María Elena Soto
- Immunology Department, National Institute of Cardiology "Ignacio Chavez", Juan Badiano 1, Sección XVI, Tlalpan, 14080 Mexico City, DF, Mexico
| | - Elizabeth Soria-Castro
- Pathology Department, National Institute of Cardiology "Ignacio Chavez", Juan Badiano 1, Sección XVI, Tlalpan, 14080 Mexico City, DF, Mexico
| | - Verónica Guarner Lans
- Physiology Department, National Institute of Cardiology "Ignacio Chavez", Juan Badiano 1, Sección XVI, Tlalpan, 14080 Mexico City, DF, Mexico
| | - Eleazar Muruato Ontiveros
- Cardiovascular Surgery Department, National Institute of Cardiology "Ignacio Chavez", Juan Badiano 1, Sección XVI, Tlalpan, 14080 Mexico City, DF, Mexico
| | - Benjamín Iván Hernández Mejía
- Cardiovascular Surgery Department, National Institute of Cardiology "Ignacio Chavez", Juan Badiano 1, Sección XVI, Tlalpan, 14080 Mexico City, DF, Mexico
| | - Humberto Jorge Martínez Hernandez
- Cardiovascular Surgery Department, National Institute of Cardiology "Ignacio Chavez", Juan Badiano 1, Sección XVI, Tlalpan, 14080 Mexico City, DF, Mexico
| | - Rodolfo Barragán García
- Cardiovascular Surgery Department, National Institute of Cardiology "Ignacio Chavez", Juan Badiano 1, Sección XVI, Tlalpan, 14080 Mexico City, DF, Mexico
| | - Valentín Herrera
- Cardiovascular Surgery Department, National Institute of Cardiology "Ignacio Chavez", Juan Badiano 1, Sección XVI, Tlalpan, 14080 Mexico City, DF, Mexico
| | - Israel Pérez-Torres
- Pathology Department, National Institute of Cardiology "Ignacio Chavez", Juan Badiano 1, Sección XVI, Tlalpan, 14080 Mexico City, DF, Mexico
| |
Collapse
|
46
|
Ergin B, Kapucu A, Demirci-Tansel C, Ince C. The renal microcirculation in sepsis. Nephrol Dial Transplant 2014; 30:169-77. [PMID: 24848133 DOI: 10.1093/ndt/gfu105] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Despite identification of several cellular mechanisms being thought to underlie the development of septic acute kidney injury (AKI), the pathophysiology of the occurrence of AKI is still poorly understood. It is clear, however, that instead of a single mechanism being responsible for its aetiology, an orchestra of cellular mechanisms failing is associated with AKI. The integrative physiological compartment where these mechanisms come together and exert their integrative deleterious action is the renal microcirculation (MC). This is why it is opportune to review the response of the renal MC to sepsis and discuss the determinants of its (dys)function and how it contributes to the pathogenesis of renal failure. A main determinant of adequate organ function is the adequate supply and utilization of oxygen at the microcirculatory and cellular level to perform organ function. The highly complex architecture of the renal microvasculature, the need to meet a high energy demand and the fact that the kidney is borderline ischaemic makes the kidney a highly vulnerable organ to hypoxaemic injury. Under normal, steady-state conditions, oxygen (O2) supply to the renal tissues is well regulated; however, under septic conditions the delicate balance of oxygen supply versus demand is disturbed due to renal microvasculature dysfunction. This dysfunction is largely due to the interaction of renal oxygen handling, nitric oxide metabolism and radical formation. Renal tissue oxygenation is highly heterogeneous not only between the cortex and medulla but also within these renal compartments. Integrative evaluation of the different determinants of tissue oxygen in sepsis models has identified the deterioration of microcirculatory oxygenation as a key component in the development AKI. It is becoming clear that resuscitation of the failing kidney needs to integratively correct the homeostasis between oxygen, and reactive oxygen and nitrogen species. Several experimental therapeutic modalities have been found to be effective in restoring microcirculatory oxygenation in parallel to improving renal function following septic AKI. However, these have to be verified in clinical studies. The development of clinical physiological biomarkers of AKI specifically aimed at the MC should form a valuable contribution to monitoring such new therapeutic modalities.
Collapse
Affiliation(s)
- Bulent Ergin
- Department of Translational Physiology, Academic Medical Center, Amsterdam, The Netherlands
| | - Aysegul Kapucu
- Department of Translational Physiology, Academic Medical Center, Amsterdam, The Netherlands Department of Biology and Zoology Division, University of Istanbul, Istanbul, Turkey
| | - Cihan Demirci-Tansel
- Department of Biology and Zoology Division, University of Istanbul, Istanbul, Turkey
| | - Can Ince
- Department of Translational Physiology, Academic Medical Center, Amsterdam, The Netherlands
| |
Collapse
|
47
|
Nasreen N, Khodayari N, Sriram PS, Patel J, Mohammed KA. Tobacco smoke induces epithelial barrier dysfunction via receptor EphA2 signaling. Am J Physiol Cell Physiol 2014; 306:C1154-66. [PMID: 24717580 DOI: 10.1152/ajpcell.00415.2012] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Erythropoietin-producing human hepatocellular carcinoma (Eph) receptors are the largest family of receptor tyrosine kinases (RTKs) that mediate various cellular and developmental processes. The degrees of expression of these key molecules control the cell-cell interactions. Although the role of Eph receptors and their ligand Ephrins is well studied in developmental processes, their function in tobacco smoke (TS)-induced epithelial barrier dysfunction is unknown. We hypothesized that TS may induce permeability in bronchial airway epithelial cell (BAEpC) monolayer by modulating receptor EphA2 expression, actin cytoskeleton, adherens junction, and focal adhesion proteins. Here we report that in BAEpCs, acute TS exposure significantly upregulated EphA2 and EphrinA1 expression, disrupted the actin filaments, decreased E-cadherin expression, and increased protein permeability, whereas the focal adhesion protein paxillin was unaffected. Silencing the receptor EphA2 expression with silencing interference RNA (siRNA) significantly attenuated TS-induced hyperpermeability in BAEpCs. In addition, when BAEpC monolayer was transfected with EphA2-expressing plasmid and treated with recombinant EphrinA1, the transepithelial electrical resistance decreased significantly. Furthermore, TS downregulated E-cadherin expression and induced hyperpermeability across BAEpC monolayer in a Erk1/Erk2, p38, and JNK MAPK-dependent manner. TS induced hyperpermeability in BAEpC monolayer by targeting cell-cell adhesions, and interestingly cell-matrix adhesions were unaffected. The present data suggest that TS causes significant damage to the BAEpCs via induction of EphA2 and downregulation of E-cadherin. Induction of EphA2 in the BAEpCs exposed to TS may be an important signaling event in the pathogenesis of TS-induced epithelial injury.
Collapse
Affiliation(s)
- Najmunnisa Nasreen
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida; and North Florida/South Georgia Veterans Health Care System, Malcom Randall Veterans Affairs Medical Center, University of Florida, Gainesville, Florida
| | - Nazli Khodayari
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida; and North Florida/South Georgia Veterans Health Care System, Malcom Randall Veterans Affairs Medical Center, University of Florida, Gainesville, Florida
| | - Peruvemba S Sriram
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida; and North Florida/South Georgia Veterans Health Care System, Malcom Randall Veterans Affairs Medical Center, University of Florida, Gainesville, Florida
| | - Jawaharlal Patel
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida; and North Florida/South Georgia Veterans Health Care System, Malcom Randall Veterans Affairs Medical Center, University of Florida, Gainesville, Florida
| | - Kamal A Mohammed
- Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Florida, Gainesville, Florida; and North Florida/South Georgia Veterans Health Care System, Malcom Randall Veterans Affairs Medical Center, University of Florida, Gainesville, Florida
| |
Collapse
|
48
|
Pulmonary Vascular Dysfunction Induced by High Tidal Volume Mechanical Ventilation*. Crit Care Med 2013; 41:e149-55. [DOI: 10.1097/ccm.0b013e318287ef4a] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
|
49
|
Courtois A, Prouillac C, Baudrimont I, Ohayon-Courtes C, Freund-Michel V, Dubois M, Lisbonne-Autissier M, Marthan R, Savineau JP, Muller B. Characterization of the components of urban particulate matter mediating impairment of nitric oxide-dependent relaxation in intrapulmonary arteries. J Appl Toxicol 2013; 34:667-74. [PMID: 23881823 DOI: 10.1002/jat.2909] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Revised: 05/17/2013] [Accepted: 06/07/2013] [Indexed: 01/28/2023]
Abstract
We have previously shown that exposure to urban particulate matter (UPM) impairs endothelial nitric oxide (NO) bioactivity in intrapulmonary arteries. As UPM is composed of heterogeneous constituents, the aim of this study was to clarify the class of pollutants responsible for such effect. Extracts (aqueous, acidic or organic) were prepared from SRM1648, an UPM sample collected in St. Louis (MO, USA). The metal composition of extracts as well as endotoxin content was determined. The effects of each extract, metal mixture and endotoxin were evaluated on endothelium-dependent relaxation to acetylcholine (reflecting endothelial NO production) in rat isolated intrapulmonary arteries. Aqueous or organic SRM1648 pretreatment altered acetylcholine-induced relaxation, similar to that induced by native SRM1648. Organic extract induced similar attenuation of acetylcholine relaxation than organic-treated SRM1648, whereas aqueous extract had no effect. Acidic pretreatment, which impoverished metal and endotoxin content of SRM1648, prevented the impairment of acetylcholine-induced relaxation. However, neither the acidic extract enriched in metals, nor a metal mixture representative of SRM1648 content, modified acetylcholine relaxation, while endotoxin impaired it. Polymyxin B, which chelates endotoxin, prevented SRM1648-induced decrease in relaxation to acetylcholine. It is concluded that SRM1648-induced impairment of endothelial NO-dependent relaxation in intrapulmonary arteries unlikely involved a soluble factor released by vascular cells during UPM exposure, but rather an organic extractible and acidic-sensitive constituents of UPM. Endotoxin, but not metals, may be responsible for UPM-induced impairment of endothelial NO-dependent relaxation.
Collapse
Affiliation(s)
- Arnaud Courtois
- Université Bordeaux Segalen, Bordeaux, F-33076, France; Inserm, U1045, Centre de Recherche Cardio-Thoracique, Bordeaux, F-33076, France
| | | | | | | | | | | | | | | | | | | |
Collapse
|
50
|
Zheng Z, Li Z, Chen S, Pan J, Ma X. Tetramethylpyrazine attenuates TNF-α-induced iNOS expression in human endothelial cells: Involvement of Syk-mediated activation of PI3K-IKK-IκB signaling pathways. Exp Cell Res 2013; 319:2145-51. [PMID: 23726836 DOI: 10.1016/j.yexcr.2013.05.018] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Revised: 05/03/2013] [Accepted: 05/21/2013] [Indexed: 02/06/2023]
Abstract
Endothelial cells produce nitric oxide (NO) by activation of constitutive nitric oxide synthase (NOS) and transcription of inducible NO synthase (iNOS). We explored the effect of tetramethylpyrazine (TMP), a compound derived from chuanxiong, on tumor necrosis factor (TNF)-α-induced iNOS in human umbilical vein endothelial cells (HUVECs) and explored the signal pathways involved by using RT-PCR and Western blot. TMP suppressed TNF-α-induced expression of iNOS by inhibiting IκB kinase (IKK) phosphorylation, IκB degradation and nuclear factor κB (NF-κB) nuclear translocation, which were required for NO gene transcription. Exposure to wortmannin abrogated IKK/IκB/NF-κB-mediated iNOS expression, suggesting activation of such a signal pathway might be phosphoinositide-3-kinase (PI3K) dependent. Spleen tyrosine kinase (Syk) inhibitor piceatannol significantly inhibited NO production. Furthermore, piceatannol obviously suppressed TNF-α-induced IκB phosphorylation and the downstream NF-κB activation, suggesting that Syk is an upstream key regulator in the activation of PI3K/IKK/IκB-mediated signaling. TMP significantly inhibited TNF-α-induced phosphorylation of Syk and PI3K. Our data indicate that TMP might repress iNOS expression, at least in part, through its inhibitory effect of Syk-mediated PI3K phosphorylation in TNF-α-stimulated HUVECs.
Collapse
Affiliation(s)
- Zhen Zheng
- Department of Intensive Care Unit, the First Affiliated Hospital, China Medical University, Bei-er Road 92, Shenyang 110001, Liaoning Province, PR China
| | | | | | | | | |
Collapse
|