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Chatterjee B, Fatima F, Seth S, Sinha Roy S. Moderate Elevation of Homocysteine Induces Endothelial Dysfunction through Adaptive UPR Activation and Metabolic Rewiring. Cells 2024; 13:214. [PMID: 38334606 PMCID: PMC10854856 DOI: 10.3390/cells13030214] [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: 11/06/2023] [Accepted: 11/25/2023] [Indexed: 02/10/2024] Open
Abstract
Elevation of the intermediate amino acid metabolite Homocysteine (Hcy) causes Hyperhomocysteinemia (HHcy), a metabolic disorder frequently associated with mutations in the methionine-cysteine metabolic cycle as well as with nutritional deficiency and aging. The previous literature suggests that HHcy is a strong risk factor for cardiovascular diseases. Severe HHcy is well-established to correlate with vascular pathologies primarily via endothelial cell death. Though moderate HHcy is more prevalent and associated with an increased risk of cardiovascular abnormalities in later part of life, its precise role in endothelial physiology is largely unknown. In this study, we report that moderate elevation of Hcy causes endothelial dysfunction through impairment of their migration and proliferation. We established that unlike severe elevation of Hcy, moderate HHcy is not associated with suppression of endothelial VEGF/VEGFR transcripts and ROS induction. We further showed that moderate HHcy induces a sub-lethal ER stress that causes defective endothelial migration through abnormal actin cytoskeletal remodeling. We also found that sub-lethal increase in Hcy causes endothelial proliferation defect by suppressing mitochondrial respiration and concomitantly increases glycolysis to compensate the consequential ATP loss and maintain overall energy homeostasis. Finally, analyzing a previously published microarray dataset, we confirmed that these hallmarks of moderate HHcy are conserved in adult endothelial cells as well. Thus, we identified adaptive UPR and metabolic rewiring as two key mechanistic signatures in moderate HHcy-associated endothelial dysfunction. As HHcy is clinically associated with enhanced vascular inflammation and hypercoagulability, identifying these mechanistic pathways may serve as future targets to regulate endothelial function and health.
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Affiliation(s)
- Barun Chatterjee
- CSIR-Institute of Genomics & Integrative Biology, New Delhi 110025, India; (B.C.); (F.F.); (S.S.)
- Academy of Scientific & Innovative Research, Ghaziabad 201002, India
| | - Fabeha Fatima
- CSIR-Institute of Genomics & Integrative Biology, New Delhi 110025, India; (B.C.); (F.F.); (S.S.)
| | - Surabhi Seth
- CSIR-Institute of Genomics & Integrative Biology, New Delhi 110025, India; (B.C.); (F.F.); (S.S.)
- Academy of Scientific & Innovative Research, Ghaziabad 201002, India
| | - Soumya Sinha Roy
- CSIR-Institute of Genomics & Integrative Biology, New Delhi 110025, India; (B.C.); (F.F.); (S.S.)
- Academy of Scientific & Innovative Research, Ghaziabad 201002, India
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Jiang QL, Li T, Xu Q, Zeng Y, Wang W, Zhang BT, Yao QP, Jiang R, Jiang J. Methyl donor diet attenuates intimal hyperplasia after vascular injury in rats. J Nutr Biochem 2024; 123:109486. [PMID: 37844765 DOI: 10.1016/j.jnutbio.2023.109486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 09/16/2023] [Accepted: 10/12/2023] [Indexed: 10/18/2023]
Abstract
Environmental factors, particularly dietary habits, play an important role in cardiovascular disease susceptibility and progression through epigenetic modification. Previous studies have shown that hyperplastic vascular intima after endarterectomy is characterized by genome-wide hypomethylation. The purpose of this study was to investigate whether methyl donor diet affects intimal hyperplasia and the possible mechanisms involved. Intimal hyperplasia was induced in SD rats by carotid artery balloon injury. From 8 d before surgery to 28 d after surgery, the animals were fed a normal diet (ND) or a methyl donor diet (MD) supplemented with folic acid, vitamin B12, choline, betaine, and zinc. Carotid artery intimal hyperplasia was observed by histology, the effect of MD on carotid protein expression was analyzed by proteomics, functional clustering, signaling pathway, and upstream-downstream relationship of differentially expressed proteins were analyzed by bioinformatics. Results showed that MD attenuated balloon injury-induced intimal hyperplasia in rat carotid arteries. Proteomic analysis showed that there were many differentially expressed proteins in the common carotid arteries of rats fed with two different diets. The differentially expressed proteins are mainly related to the composition and function of the extracellular matrix (EMC), and changes in the EMC can lead to vascular remodeling by affecting fibrosis and stiffness of the blood vessel wall. Changes in the levels of vasculotropic proteins such as S100A9, ILF3, Serpinh1, Fbln5, LOX, HSPG2, and Fmod may be the reason why MD attenuates intimal hyperplasia. Supplementation with methyl donor nutrients may be a beneficial measure to prevent pathological vascular remodeling after injury.
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Affiliation(s)
- Qi-Lan Jiang
- Department of Clinical Nutrition, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Tao Li
- Key Laboratory of Medical Electrophysiology, Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease/Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, China
| | - Qin Xu
- Department of General Surgery (Thyroid Surgery), the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yang Zeng
- Department of Orthodontics, the Affiliated Stomatology Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Wei Wang
- Department of General Surgery (Thyroid Surgery), the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Bo-Tao Zhang
- Department of General Surgery (Thyroid Surgery), the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Qing-Ping Yao
- Institute of Mechanobiology & Medical Engineering, School of Life Science & Biotechnology, Shanghai Jiao Tong University, Shanghai, China.
| | - Rui Jiang
- Department of Urology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
| | - Jun Jiang
- Department of General Surgery (Thyroid Surgery), the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
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D’Amico R, Cordaro M, Fusco R, Peritore AF, Genovese T, Gugliandolo E, Crupi R, Mandalari G, Caccamo D, Cuzzocrea S, Di Paola R, Siracusa R, Impellizzeri D. Consumption of Cashew ( Anacardium occidentale L.) Nuts Counteracts Oxidative Stress and Tissue Inflammation in Mild Hyperhomocysteinemia in Rats. Nutrients 2022; 14:1474. [PMID: 35406088 PMCID: PMC9002620 DOI: 10.3390/nu14071474] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 03/28/2022] [Accepted: 03/30/2022] [Indexed: 02/01/2023] Open
Abstract
Hyperhomocysteinemia (HHcy) is a methionine metabolism problem that causes a variety of inflammatory illnesses. Oxidative stress is among the processes thought to be involved in the pathophysiology of the damage produced by HHcy. HHcy is likely to involve the dysfunction of several organs, such as the kidney, liver, or gut, which are currently poorly understood. Nuts are regarded as an important part of a balanced diet since they include protein, good fatty acids, and critical nutrients. The aim of this work was to evaluate the anti-inflammatory and antioxidant effects of cashew nuts in HHcy induced by oral methionine administration for 30 days, and to examine the possible pathways involved. In HHcy rats, cashew nuts (100 mg/kg orally, daily) were able to counteract clinical biochemical changes, oxidative and nitrosative stress, reduced antioxidant enzyme levels, lipid peroxidation, proinflammatory cytokine release, histological tissue injuries, and apoptosis in the kidney, colon, and liver, possibly by the modulation of the antioxidant nuclear factor erythroid 2-related factor 2 NRF-2 and inflammatory nuclear factor NF-kB pathways. Thus, the results suggest that the consumption of cashew nuts may be beneficial for the treatment of inflammatory conditions associated with HHcy.
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Affiliation(s)
- Ramona D’Amico
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Via F. Stagno D’Alcontres 31, 98166 Messina, Italy; (R.D.); (A.F.P.); (T.G.); (G.M.); (R.S.); (D.I.)
| | - Marika Cordaro
- Department of Biomedical, Dental and Morphological and Functional Imaging, University of Messina, Via Consolare Valeria, 98125 Messina, Italy; (M.C.); (D.C.)
| | - Roberta Fusco
- Department of Clinical and Experimental Medicine, University of Messina, 98125 Messina, Italy;
| | - Alessio Filippo Peritore
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Via F. Stagno D’Alcontres 31, 98166 Messina, Italy; (R.D.); (A.F.P.); (T.G.); (G.M.); (R.S.); (D.I.)
| | - Tiziana Genovese
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Via F. Stagno D’Alcontres 31, 98166 Messina, Italy; (R.D.); (A.F.P.); (T.G.); (G.M.); (R.S.); (D.I.)
| | - Enrico Gugliandolo
- Department of Veterinary Sciences, University of Messina, 98168 Messina, Italy; (E.G.); (R.C.)
| | - Rosalia Crupi
- Department of Veterinary Sciences, University of Messina, 98168 Messina, Italy; (E.G.); (R.C.)
| | - Giuseppina Mandalari
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Via F. Stagno D’Alcontres 31, 98166 Messina, Italy; (R.D.); (A.F.P.); (T.G.); (G.M.); (R.S.); (D.I.)
| | - Daniela Caccamo
- Department of Biomedical, Dental and Morphological and Functional Imaging, University of Messina, Via Consolare Valeria, 98125 Messina, Italy; (M.C.); (D.C.)
| | - Salvatore Cuzzocrea
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Via F. Stagno D’Alcontres 31, 98166 Messina, Italy; (R.D.); (A.F.P.); (T.G.); (G.M.); (R.S.); (D.I.)
- Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, 1402 South Grand Blvd, St. Louis, MO 63104, USA
| | - Rosanna Di Paola
- Department of Veterinary Sciences, University of Messina, 98168 Messina, Italy; (E.G.); (R.C.)
| | - Rosalba Siracusa
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Via F. Stagno D’Alcontres 31, 98166 Messina, Italy; (R.D.); (A.F.P.); (T.G.); (G.M.); (R.S.); (D.I.)
| | - Daniela Impellizzeri
- Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Via F. Stagno D’Alcontres 31, 98166 Messina, Italy; (R.D.); (A.F.P.); (T.G.); (G.M.); (R.S.); (D.I.)
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Grambow E, Klee G, Klar E, Vollmar B. The slow releasing hydrogen sulfide donor GYY4137 reduces neointima formation upon FeCl3 injury of the carotid artery in mice. Clin Hemorheol Microcirc 2020; 75:409-417. [PMID: 31929150 DOI: 10.3233/ch-190747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
INTRODUCTION Neointima formation is closely linked to vascular stenosis and occurs after endothelial damage. Hydrogen sulfide is an endogenous pleiotropic mediator with numerous positive effects on the cardio vascular system. OBJECTIVE This study evaluates the effect of the slow releasing hydrogen sulfide donor GYY4137 (GYY) on neointimal formation in vivo. METHODS The effect of GYY on neointimal formation in the carotid artery was studied in the FeCl3 injury model in GYY- or vehicle-treated mice. The carotid arteries were studied at days 7 and 21 after treatment by means of histology and immunohistochemistry for proliferating cell nuclear antigen (PCNA) and alpha smooth muscle actin (α-SMA). RESULTS GYY treatment significantly reduced the maximal diameter and the area of the newly formed neointima on both days 7 and 21 when compared to vehicle treatment. GYY additionally reduced the number of PCNA- and α-SMA-positive cells within the neointima on day 21 after FeCl3 injury of the carotid artery. CONCLUSIONS Summarizing, single treatment with the slow releasing hydrogen sulfide donor GYY reduced the extent of the newly formed neointima by affecting the cellular proliferation at the site of vascular injury.
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Affiliation(s)
- Eberhard Grambow
- Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany.,Department of General, Visceral, Vascular and Transplantation Surgery, Rostock University Medical Center, Rostock, Germany
| | - Gina Klee
- Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
| | - Ernst Klar
- Department of General, Visceral, Vascular and Transplantation Surgery, Rostock University Medical Center, Rostock, Germany
| | - Brigitte Vollmar
- Institute for Experimental Surgery, Rostock University Medical Center, Rostock, Germany
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Rejuvenated Circulating Endothelial Progenitor Cells and Nitric Oxide in Premenopausal Women with Hyperhomocysteinemia. Cardiol Res Pract 2020; 2020:5010243. [PMID: 33204526 PMCID: PMC7657675 DOI: 10.1155/2020/5010243] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 09/08/2020] [Accepted: 09/24/2020] [Indexed: 02/06/2023] Open
Abstract
Hyperhomocysteinemia (HHcy) induced endothelial dysfunction is associated with disturbance in circulating endothelial progenitor cells (EPCs). Nevertheless, whether this unfavorable effect of HHcy on circulating EPCs also exists in premenopausal women is still unknown. Therefore, this leaves an area for the investigation of the difference on the number and activity of circulating EPCs in premenopausal women with hyperhomocysteinemia and its underlying mechanism. The number of circulating EPCs was measured by fluorescence-activated cell sorter analysis, as well as DiI-acLDL and lectin fluorescent staining. The migration and proliferation of circulating were evaluated by the Transwell chamber assay and MTT. Additionally, the endothelial function and levels of nitric oxide (NO), VEGF, and GM-CSF in plasma and culture medium were determined. The number or activity of circulating EPCs and flow-mediated dilatation (FMD) in premenopausal women with or without HHcy were higher than those in postmenopausal women. However, no significant effect of HHcy on the number or activity of circulating EPCs in premenopausal women was observed. A similar alteration in NO level between the four groups was observed. There was a correlation between FMD and the number or activity of EPCs, as well as NO level in plasma or secretion by EPCs. For the first time, our findings illuminated the quantitive or qualitative alterations of circulating EPCs and endothelial function in premenopausal patients with HHcy are preserved, which was associated with retained NO production. The recuperated endothelial repair capacity is possibly the potential mechanism interpreting cardiovascular protection in premenopausal women with HHcy.
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Hyperhomocysteinemia leads to exacerbation of ischemic brain damage: Role of GluN2A NMDA receptors. Neurobiol Dis 2019; 127:287-302. [PMID: 30885791 DOI: 10.1016/j.nbd.2019.03.012] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Revised: 02/19/2019] [Accepted: 03/14/2019] [Indexed: 11/24/2022] Open
Abstract
Hyperhomocysteinemia has been implicated in several neurodegenerative disorders including ischemic stroke. However, the pathological consequences of ischemic insult in individuals predisposed to hyperhomocysteinemia and the associated etiology are unknown. In this study, we evaluated the outcome of transient ischemic stroke in a rodent model of hyperhomocysteinemia, developed by subcutaneous implantation of osmotic pumps containing L-homocysteine into male Wistar rats. Our findings show a 42.3% mortality rate in hyperhomocysteinemic rats as compared to 7.7% in control rats. Magnetic resonance imaging of the brain in the surviving rats shows that mild hyperhomocysteinemia leads to exacerbation of ischemic injury within 24 h, which remains elevated over time. Behavioral studies further demonstrate significant deficit in sensorimotor functions in hyperhomocysteinemic rats compared to control rats. Using pharmacological inhibitors targeting the NMDAR subtypes, the study further demonstrates that inhibition of GluN2A-containing NMDARs significantly reduces ischemic brain damage in hyperhomocysteinemic rats but not in control rats, indicating that hyperhomocysteinemia-mediated exacerbation of ischemic brain injury involves GluN2A-NMDAR signaling. Complementary studies in GluN2A-knockout mice show that in the absence of GluN2A-NMDARs, hyperhomocysteinemia-associated exacerbation of ischemic brain injury is blocked, confirming that GluN2A-NMDAR activation is a critical determinant of the severity of ischemic damage under hyperhomocysteinemic conditions. Furthermore, at the molecular level we observe GluN2A-NMDAR dependent sustained increase in ERK MAPK phosphorylation under hyperhomocysteinemic condition that has been shown to be involved in homocysteine-induced neurotoxicity. Taken together, the findings show that hyperhomocysteinemia triggers a unique signaling pathway that in conjunction with ischemia-induced pathways enhance the pathology of stroke under hyperhomocysteinemic conditions.
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Liu X, Qin Z, Liu C, Song M, Luo X, Zhao H, Qian D, Chen J, Huang L. Nox4 and soluble epoxide hydrolase synergistically mediate homocysteine-induced inflammation in vascular smooth muscle cells. Vascul Pharmacol 2019; 120:106544. [PMID: 30610956 DOI: 10.1016/j.vph.2019.01.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 12/05/2018] [Accepted: 01/01/2019] [Indexed: 01/03/2023]
Abstract
BACKGROUND Hyperhomocysteinemia leads to a vascular smooth muscle cell (VSMC) inflammatory response. Meanwhile, Nox4 dependent reactive oxygen species (ROS) signaling and soluble epoxide hydrolase (sEH)/epoxyeicosatrienoic acids (EETs) are both involved in vascular inflammation. Herein, we hypothesized that Nox4 and soluble epoxide hydrolase cross regulated during homocysteine-induced VSMC inflammation. METHODS AND RESULTS In cultured VSMCs, the expression of the inflammatory factors VCAM1 and ICAM1 was measured by real-time PCR and Western blotting, while supernatant MCP1 was measured by ELISA. Upon VSMC stimulation with 50 μΜ homocysteine, we observed the VCAM1 and ICAM1 mRNA levels were increased by 1.15 and 1.0 folds, respectively. The MCP1 levels in the supernatant of cultured VSMCs treated with 100 μΜ increased to 1.76 folds. As expected, homocysteine induced Nox4 expression and Nox4-dependent ROS generation. The sEH expression was also upregulated in the presence of homocysteine in a dose-dependent manner. Furthermore, we knocked down Nox4 with siRNA. Knockdown of Nox4 decreased ROS generation and homocysteine-induced sEH expression. Overexpression of Nox4 with an adenovirus stimulated sEH expression. Similarly, knockdown or chemical inhibition of sEH blunted the upregulation of Nox4 by homocysteine. In vivo, in homocysteine-fed mice, concomitant upregulation of Nox4 and sEH was associated with increased VCAM1 and ICAM1 expression in the aortic wall. CONCLUSIONS The inflammatory response induced by homocysteine in VSMCs was accompanied by Nox4 and sEH upregulation. Nox4 and soluble epoxide hydrolase synergistically contribute to homocysteine-induced inflammation.
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Affiliation(s)
- Xi Liu
- Department of Cardiology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Zhexue Qin
- Department of Cardiology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Chuan Liu
- Department of Cardiology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Mingbao Song
- Department of Cardiology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Xiaolin Luo
- Department of Cardiology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Hongqing Zhao
- Department of Cardiology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Dehui Qian
- Department of Cardiology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Jianfei Chen
- Department of Cardiology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China
| | - Lan Huang
- Department of Cardiology, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing 400037, China.
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Yang M, Fan Z, Wang F, Tian ZH, Ma B, Dong B, Li Z, Zhang M, Zhao W. BMP-2 enhances the migration and proliferation of hypoxia-induced VSMCs via actin cytoskeleton, CD44 and matrix metalloproteinase linkage. Exp Cell Res 2018; 368:248-257. [DOI: 10.1016/j.yexcr.2018.05.004] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2017] [Revised: 05/03/2018] [Accepted: 05/06/2018] [Indexed: 12/24/2022]
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Hendrix P, Foreman PM, Harrigan MR, Fisher WS, Vyas NA, Lipsky RH, Lin M, Walters BC, Tubbs RS, Shoja MM, Pittet JF, Mathru M, Griessenauer CJ. Association of cystathionine beta-synthase polymorphisms and aneurysmal subarachnoid hemorrhage. J Neurosurg 2018; 128:1771-1777. [DOI: 10.3171/2017.2.jns162933] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
OBJECTIVECystathionine β-synthase (CBS) is involved in homocysteine and hydrogen sulfide (H2S) metabolism. Both products have been implicated in the pathophysiology of cerebrovascular diseases. The impact of CBS polymorphisms on aneurysmal subarachnoid hemorrhage (aSAH) and its clinical sequelae is poorly understood.METHODSBlood samples from all patients enrolled in the CARAS (Cerebral Aneurysm Renin Angiotensin System) study were used for genetic evaluation. The CARAS study prospectively enrolled aSAH patients at 2 academic institutions in the United States from 2012 to 2015. Common CBS polymorphisms were detected using 5′exonuclease genotyping assays. Analysis of associations between CBS polymorphisms and aSAH was performed.RESULTSSamples from 149 aSAH patients and 50 controls were available for analysis. In multivariate logistic regression analysis, the insertion allele of the 844ins68 CBS insertion polymorphism showed a dominant effect on aSAH. The GG genotype of the CBS G/A single nucleotide polymorphism (rs234706) was independently associated with unfavorable functional outcome (modified Rankin Scale Score 3–6) at discharge and last follow-up, but not clinical vasospasm or delayed cerebral ischemia (DCI).CONCLUSIONSThe insertion allele of the 844ins68 CBS insertion polymorphism was independently associated with aSAH while the GG genotype of rs234706 was associated with an unfavorable outcome both at discharge and last follow-up. Increased CBS activity may exert its neuroprotective effects through alteration of H2S levels, and independent of clinical vasospasm and DCI.
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Affiliation(s)
- Philipp Hendrix
- 1Department of Neurosurgery, Saarland University Medical Center and Saarland University Faculty of Medicine, Homburg/Saar, Germany
| | - Paul M. Foreman
- 2Department of Neurosurgery, University of Alabama at Birmingham, Alabama
| | - Mark R. Harrigan
- 2Department of Neurosurgery, University of Alabama at Birmingham, Alabama
| | - Winfield S. Fisher
- 2Department of Neurosurgery, University of Alabama at Birmingham, Alabama
| | - Nilesh A. Vyas
- 3Department of Neurosciences, Inova Health System, Falls Church
| | - Robert H. Lipsky
- 3Department of Neurosciences, Inova Health System, Falls Church
- 4Department of Molecular Neuroscience, George Mason University, Fairfax, Virginia
| | - Mingkuan Lin
- 4Department of Molecular Neuroscience, George Mason University, Fairfax, Virginia
| | - Beverly C. Walters
- 2Department of Neurosurgery, University of Alabama at Birmingham, Alabama
- 4Department of Molecular Neuroscience, George Mason University, Fairfax, Virginia
| | | | - Mohammadali M. Shoja
- 6Neuroscience Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Mali Mathru
- 7Department of Anesthesiology, University of Alabama at Birmingham, Alabama
| | - Christoph J. Griessenauer
- 8Neurosurgical Service, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and
- 9Department of Neurosurgery, Geisinger Health System, Danville, Pennsylvania
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Kumar A, Palfrey HA, Pathak R, Kadowitz PJ, Gettys TW, Murthy SN. The metabolism and significance of homocysteine in nutrition and health. Nutr Metab (Lond) 2017; 14:78. [PMID: 29299040 PMCID: PMC5741875 DOI: 10.1186/s12986-017-0233-z] [Citation(s) in RCA: 206] [Impact Index Per Article: 25.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 12/07/2017] [Indexed: 12/31/2022] Open
Abstract
An association between arteriosclerosis and homocysteine (Hcy) was first demonstrated in 1969. Hcy is a sulfur containing amino acid derived from the essential amino acid methionine (Met). Hyperhomocysteinemia (HHcy) was subsequently shown in several age-related pathologies such as osteoporosis, Alzheimer's disease, Parkinson's disease, stroke, and cardiovascular disease (CVD). Also, Hcy is associated with (but not limited to) cancer, aortic aneurysm, hypothyroidism and end renal stage disease to mention some. The circulating levels of Hcy can be increased by defects in enzymes of the metabolism of Met, deficiencies of vitamins B6, B12 and folate or by feeding Met enriched diets. Additionally, some of the pharmaceuticals currently in clinical practice such as lipid lowering, and anti-Parkinsonian drugs are known to elevate Hcy levels. Studies on supplementation with folate, vitamins B6 and B12 have shown reduction in Hcy levels but concomitant reduction in certain associated pathologies have not been definitive. The enormous importance of Hcy in health and disease is illustrated by its prevalence in the medical literature (e.g. > 22,000 publications). Although there are compelling data in favor of Hcy as a modifiable risk factor, the debate regarding the significance of Hcy mediated health effects is still ongoing. Despite associations between increased levels of Hcy with several pathologies being well documented, whether it is a causative factor, or an effect remains inconclusive. The present review though not exhaustive, is focused on several important aspects of Hcy metabolism and their relevance to health.
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Affiliation(s)
- Avinash Kumar
- Environmental Toxicology Department, Southern University and A&M College, Baton Rouge, LA 70813 USA
| | - Henry A. Palfrey
- Environmental Toxicology Department, Southern University and A&M College, Baton Rouge, LA 70813 USA
| | - Rashmi Pathak
- Environmental Toxicology Department, Southern University and A&M College, Baton Rouge, LA 70813 USA
| | - Philip J. Kadowitz
- Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA USA
| | - Thomas W. Gettys
- Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, Baton Rouge, LA USA
| | - Subramanyam N. Murthy
- Environmental Toxicology Department, Southern University and A&M College, Baton Rouge, LA 70813 USA
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Lan TH, Xu DP, Huang MT, Song JX, Wu HL, Li M. Ginsenoside Rb1 prevents homocysteine-induced EPC dysfunction via VEGF/p38MAPK and SDF-1/CXCR4 activation. Sci Rep 2017; 7:13061. [PMID: 29026158 PMCID: PMC5638839 DOI: 10.1038/s41598-017-13436-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2017] [Accepted: 09/25/2017] [Indexed: 11/17/2022] Open
Abstract
Hyperhomocystinemia (HHcy) is known as an independent risk factor for cardiovascular disease. Our previous study showed that ginsenoside Rb1, the major active constituent of ginseng, prevents homocysteine (Hcy)-induced endothelial damage. However, the role of ginsenoside Rb1 in Hcy-induced dysfunction in endothelial progenitor cells (EPCs) remains unknown. In the study, we found that ginsenoside Rb1 reversed the Hcy-induced impairment of adhesive and migratory ability in EPCs which were significantly abolished by CXCR4 antagonist AMD3100 and VEGFR2 inhibitor SU5416. Ginsenoside Rb1 significantly reversed Hcy-induced SDF-1 reduction in the supernatant and in the serum. Ginsenoside Rb1 reversed downregulation of SDF-1 and VEGFR2 protein expression, inhibition of p38MAPK phosphorylation induced by Hcy. Re-endothelialization in balloon-injured carotid arteries significantly increased with EPCs transplant, and was even better with Rb1 treatment. This effect was significantly abolished by AMD3100. AMD3100 also decreased the number of CM-DiI labeled EPCs in injured arteries. Here we show for the first time that Rb1 prevents Hcy-induced EPC dysfunction via VEGF/p38MAPK and SDF-1/CXCR4 activation. These findings demonstrate a novel mechanism of the action of Rb1 that may have value in prevention of HHcy associated cardiovascular disease.
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Affiliation(s)
- Tao-Hua Lan
- Department of Cardiology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, P. R. China.,School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong
| | - Dan-Ping Xu
- Department of Cardiology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, P. R. China
| | - Man-Ting Huang
- Department of Cardiology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, P. R. China
| | - Ju-Xian Song
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong
| | - Huan-Lin Wu
- Department of Cardiology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, P. R. China.
| | - Min Li
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, Hong Kong.
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12
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Pang X, Si J, Xu S, Li Y, Liu J. Simvastatin inhibits homocysteine-induced CRP generation via interfering with the ROS-p38/ERK1/2 signal pathway in rat vascular smooth muscle cells. Vascul Pharmacol 2017; 88:42-47. [DOI: 10.1016/j.vph.2016.12.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Revised: 11/22/2016] [Accepted: 12/03/2016] [Indexed: 12/14/2022]
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Yeh JK, Chen CC, Hsieh MJ, Tsai ML, Yang CH, Chen DY, Chang SH, Wang CY, Lee CH, Hsieh IC. Impact of Homocysteine Level on Long-term Cardiovascular Outcomes in Patients after Coronary Artery Stenting. J Atheroscler Thromb 2016; 24:696-705. [PMID: 27803490 PMCID: PMC5517543 DOI: 10.5551/jat.36434] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Aim: The prognostic value of homocysteine (HCY) in patients with coronary artery diseases (CAD) is still controversial. The objective of this study was to investigate whether elevated HCY level at admission predict long-term outcomes in patients after percutaneous coronary interventions (PCI) with coronary artery stenting. Methods: From the institutional registry of Cardiovascular Atherosclerosis and Percutaneous TrAnsluminal INterventions (CAPTAIN), we enrolled a total of 1,307 patients with documented CAD undergone PCI with bare metal stents from July 2003 to December 2014. They were divided into two groups according to the fasting plasma HCY levels before catheterization: group I (883 patients, < 12 µmol/L) and group II (424 patients, ≥ 12 µmol/L). The primary endpoint was occurrence of major adverse cardiac events (MACE), including cardiac death, nonfatal myocardial infarction, stroke, target lesion revascularization, new lesion stenting, and requiring bypass surgery. Results: After a mean follow-up period of 58 ± 41 months, the group II patients had a higher MACE rate (33.3% vs. 25.6%, p = 0.005). The main differences between two groups were cardiac death (8.0% vs. 3.4%, p = 0.001) and new lesion stenting (13.6% vs. 9.5%, p = 0.034). The risks of long-term MACE remained significantly higher in patients with elevated HCY level (≥ 12 µmol/L) after adjusting for clinical variables, with a hazard ratio of 1.29 (95% CI, 1.02–1.64, p = 0.036). Conclusions: Elevated HCY level (≥ 12 µmol/L) was independently associated with increased risk of long-term cardiovascular events in patients after coronary artery bare metal stents implantations. Thus, hyperhomocysteinemia may remain a useful prognostic marker for the risk assessment in clinical care of CAD patients.
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Affiliation(s)
- Jih-Kai Yeh
- Department of Cardiology, Percutaneous Coronary Intervention Center, Chang Gung Memorial Hospital
| | - Chun-Chi Chen
- Department of Cardiology, Percutaneous Coronary Intervention Center, Chang Gung Memorial Hospital
| | - Ming-Jer Hsieh
- Department of Cardiology, Percutaneous Coronary Intervention Center, Chang Gung Memorial Hospital
| | - Ming-Lung Tsai
- Department of Cardiology, Percutaneous Coronary Intervention Center, Chang Gung Memorial Hospital
| | - Chia-Hung Yang
- Department of Cardiology, Percutaneous Coronary Intervention Center, Chang Gung Memorial Hospital
| | - Dong-Yi Chen
- Department of Cardiology, Percutaneous Coronary Intervention Center, Chang Gung Memorial Hospital
| | - Shang-Hung Chang
- Department of Cardiology, Percutaneous Coronary Intervention Center, Chang Gung Memorial Hospital
| | - Chao-Yung Wang
- Department of Cardiology, Percutaneous Coronary Intervention Center, Chang Gung Memorial Hospital
| | - Cheng-Hung Lee
- Department of Cardiology, Percutaneous Coronary Intervention Center, Chang Gung Memorial Hospital
| | - I-Chang Hsieh
- Department of Cardiology, Percutaneous Coronary Intervention Center, Chang Gung Memorial Hospital
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Samson RH, Yungst Z, Showalter DP. Homocysteine, a Risk Factor for Carotid Atherosclerosis, Is Not a Risk Factor for Early Recurrent Carotid Stenosis Following Carotid Endarterectomy. Vasc Endovascular Surg 2016; 38:345-8. [PMID: 15306952 DOI: 10.1177/153857440403800406] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Homocysteine has been proposed as a risk factor for atherosclerotic disease and recurrent coronary stenosis due to neointimal hyperplasia following angioplasty. In order to evaluate homocysteine's role in human carotid neointimal hyperplasia, we have compared homocysteine levels in patients who have not developed restenosis with those who have within 2 years of carotid endarterectomy (CEA). One hundred and fifty-four patients were divided into 3 groups based on duplex scans performed 2 years after CEA. Group I (88) were patients in whom all scans showed no evidence of restenosis. Group II (35) patients exhibited some restenosis, but this did not exceed 49% diameter reduction based on our duplex criteria. Group III (31) patients developed a restenosis of >50% within 2 years. One hundred and thirteen Dacron patches (73 Group I [83%], 22 Group II [63%], and 18 Group III [58%]) were used according to surgeon preference but did not affect the statistical relevance of homocysteine evaluation. The groups were otherwise identical in terms of age, sex, smoking history, and cholesterol levels. All patients were receiving antiplatelet medication postoperatively, and none had consumed added pharmacologic folate. The average homocysteine value for the entire study group was elevated at 12.5 µmol/L. The homocysteine values for the 3 groups were not statistically different (p>1): (I, 12.5; II, 12.2; and III, 12.9 µmol/L). Elevated homocysteine levels (>10 µmol/L) appear to be associated with carotid atherosclerosis, but at levels < 30 µmol/L do not appear to play a role in restenosis following CEA.
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15
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Deminice R, Ribeiro DF, Frajacomo FTT. The Effects of Acute Exercise and Exercise Training on Plasma Homocysteine: A Meta-Analysis. PLoS One 2016; 11:e0151653. [PMID: 26986570 PMCID: PMC4795785 DOI: 10.1371/journal.pone.0151653] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2015] [Accepted: 03/02/2016] [Indexed: 12/29/2022] Open
Abstract
Background Although studies have demonstrated that physical exercise alters homocysteine levels in the blood, meta-analyses of the effects of acute exercise and exercise training on homocysteine blood concentration have not been performed, especially regarding the duration and intensity of exercise, which could affect homocysteine levels differently. Objective The aim of this meta-analysis was to ascertain the effects of acute exercise and exercise training on homocysteine levels in the blood. Method A review was conducted according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses using the online databases PubMed, SPORTDiscus, and SciELO to identify relevant studies published through June 2015. Review Manager was used to calculate the effect size of acute exercise and exercise training using the change in Hcy plasmaserum concentration from baseline to post-acute exercise and trained vs. sedentary control groups, respectively. Weighted mean differences were calculated using random effect models. Results Given the abundance of studies, acute exercise trials were divided into two subgroups according to exercise volume and intensity, whereas the effects of exercise training were analyzed together. Overall, 22 studies with a total of 520 participants indicated increased plasma homocysteine concentration after acute exercise (1.18 μmol/L, 95% CI: 0.71 to 1.65, p < .01). Results of a subgroup analysis indicated that either long-term exercise of low-to-moderate intensity (1.39 μmol/L, 95% CI: 0.9 to 1.89, p < .01) or short-term exercise of high intensity (0.83 μmol/L, 95% CI: 0.19 to 1.40, p < .01) elevated homocysteine levels in the blood. Increased homocysteine induced by exercise was significantly associated with volume of exercise, but not intensity. By contrast, resistance training reduced plasma homocysteine concentration (-1.53 μmol/L, 95% CI: -2.77 to -0.28, p = .02), though aerobic training did not. The cumulative results of the seven studies with a total of 230 participants in exercise training analysis did not demonstrate a significant impact on homocysteine levels in the blood (-0.56 μmol/L, 95% CI: -1.61 to 0.50, p = .23). Conclusions Current evidence demonstrates that acute exercise increases homocysteine levels in the blood independent of exercise duration and intensity. Resistance, but not aerobic training decreases plasma homocysteine levels.
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Affiliation(s)
- Rafael Deminice
- Department of Physical Education, State University of Londrina, Londrina-PR, Brazil
- * E-mail:
| | - Diogo Farias Ribeiro
- Department of Physical Education, State University of Londrina, Londrina-PR, Brazil
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16
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A Diagnostic and Therapeutic Approach to Arrhythmias in Cardiac Sarcoidosis. CURRENT TREATMENT OPTIONS IN CARDIOVASCULAR MEDICINE 2016; 18:16. [PMID: 26874704 DOI: 10.1007/s11936-016-0439-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OPINION STATEMENT Cardiac sarcoidosis is a protean disease, capable of causing nearly any cardiac abnormality. Electrical abnormalities including heart block and ventricular tachyarrhythmias are some of the most feared manifestations of cardiac sarcoidosis. Despite increasing awareness, cardiac sarcoidosis remains underdiagnosed in clinical practice, and as a result, many patients do not receive potentially disease-altering immunosuppressant therapy. In this review, we discuss cardiac sarcoidosis and its management, focusing diagnostic and therapeutic approaches to arrhythmias in cardiac sarcoidosis.
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17
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Selhub J, Troen AM. Sulfur amino acids and atherosclerosis: a role for excess dietary methionine. Ann N Y Acad Sci 2015; 1363:18-25. [PMID: 26647293 DOI: 10.1111/nyas.12962] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The homocysteine theory of arteriosclerosis received credence when it was shown that after a methionine load, circulating homocysteine-cysteine concentrations were higher in cardiovascular disease patients than in healthy controls. Subsequent studies showing associations between homocysteine and coronary artery disease, stroke and cognitive impairment, relied on small increases in homocysteine concentration unlike the very high homocysteine seen in the rare genetic disorders that lead to homocystinuria and much higher homocysteine levels. Subsequent studies in cell culture, animals, and humans showed that a variety of cardiovascular adverse effects of "high homocysteine" introduced either as a nonphysiological bolus or as a methionine load led to high homocysteine. We fed apolipoprotein E-deficient mice diets designed to achieve three conditions: (1) high methionine intake with normal blood homocysteine, (2) high methionine intake with B vitamin deficiency and hyperhomocysteinemia, and (3) normal methionine intake with both B vitamin deficiency and hyperhomocysteinemia. We found that the mice fed methionine-rich diets had significant atheromatous pathology in the aortic arch even with normal plasma homocysteine levels. Mice fed B vitamin-deficient diets developed severe hyperhomocysteinemia but without any increase in vascular pathology. Our findings suggest that even moderate increases in methionine intake are atherogenic in susceptible mice while high plasma homocysteine is not.
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Affiliation(s)
- Jacob Selhub
- Jean Mayer Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts
| | - Aron M Troen
- Nutrition and Brain Health Laboratory, The Institute of Biochemistry Food and Nutrition Science, The Robert H. Smith Faculty of Agriculture Food and the Environment, The Hebrew University of Jerusalem, Israel
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18
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Pang X, Liu J, Li Y, Zhao J, Zhang X. Emodin Inhibits Homocysteine-Induced C-Reactive Protein Generation in Vascular Smooth Muscle Cells by Regulating PPARγ Expression and ROS-ERK1/2/p38 Signal Pathway. PLoS One 2015; 10:e0131295. [PMID: 26131983 PMCID: PMC4488440 DOI: 10.1371/journal.pone.0131295] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 06/01/2015] [Indexed: 11/30/2022] Open
Abstract
Atherosclerosis is an inflammatory disease. As an inflammatory molecule, C-reactive protein (CRP) plays a direct role in atherogenesis. It is known that the elevated plasma homocysteine (Hcy) level is an independent risk factor for atherosclerosis. We previously reported that Hcy produces a pro-inflammatory effect by inducing CRP expression in vascular smooth muscle cells (VSMCs). In the present study, we observed effect of emodin on Hcy-induced CRP expression in rat VSMCs and molecular mechanisms. The in vitro results showed that pretreatment of VSMCs with emodin inhibited Hcy-induced mRNA and protein expression of CRP in a concentration-dependent manner. The in vivo experiments displayed that emodin not only inhibited CRP expression in the vessel walls in mRNA and protein levels, but also reduced the circulating CRP level in hyperhomocysteinemic rats. Further study revealed that emodin diminished Hcy-stimulated generation of reactive oxygen species (ROS), attenuated Hcy-activated phosphorylation of ERK1/2 and p38, and upregulated Hcy-inhibited expression of peroxisome proliferator-activated receptor gamma (PPARγ) in VSMCs. These demonstrate that emodin is able to inhibit Hcy-induced CRP generation in VSMCs, which is related to interfering with ROS-ERK1/2/p38 signal pathway and upregulating PPARγ expression. The present study provides new evidence for the anti-inflammatory and anti-atherosclerotic effects of emodin.
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MESH Headings
- Animals
- Anti-Inflammatory Agents, Non-Steroidal/pharmacology
- Aorta, Thoracic/cytology
- Aorta, Thoracic/drug effects
- Aorta, Thoracic/metabolism
- C-Reactive Protein/antagonists & inhibitors
- C-Reactive Protein/genetics
- C-Reactive Protein/metabolism
- Emodin/pharmacology
- Gene Expression Regulation
- Homocysteine/antagonists & inhibitors
- Homocysteine/pharmacology
- Hyperhomocysteinemia/drug therapy
- Hyperhomocysteinemia/genetics
- Hyperhomocysteinemia/metabolism
- Hyperhomocysteinemia/pathology
- Male
- Mitogen-Activated Protein Kinase 1/antagonists & inhibitors
- Mitogen-Activated Protein Kinase 1/genetics
- Mitogen-Activated Protein Kinase 1/metabolism
- Mitogen-Activated Protein Kinase 3/antagonists & inhibitors
- Mitogen-Activated Protein Kinase 3/genetics
- Mitogen-Activated Protein Kinase 3/metabolism
- Muscle, Smooth, Vascular/cytology
- Muscle, Smooth, Vascular/drug effects
- Muscle, Smooth, Vascular/metabolism
- Myocytes, Smooth Muscle/cytology
- Myocytes, Smooth Muscle/drug effects
- Myocytes, Smooth Muscle/metabolism
- PPAR gamma/agonists
- PPAR gamma/genetics
- PPAR gamma/metabolism
- Phosphorylation/drug effects
- Primary Cell Culture
- Rats
- Rats, Sprague-Dawley
- Reactive Oxygen Species/antagonists & inhibitors
- Reactive Oxygen Species/metabolism
- Signal Transduction
- p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors
- p38 Mitogen-Activated Protein Kinases/genetics
- p38 Mitogen-Activated Protein Kinases/metabolism
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Affiliation(s)
- Xiaoming Pang
- Department of Pharmacology, Xi’an Jiaotong University School of Medicine, Xi’an, China
- Department of Clinical Pharmacy, Central Hospital of Zibo, Zibo, China
| | - Juntian Liu
- Department of Pharmacology, Xi’an Jiaotong University School of Medicine, Xi’an, China
- * E-mail:
| | - Yuxia Li
- Department of Clinical Pharmacy, Central Hospital of Zibo, Zibo, China
| | - Jingjing Zhao
- Department of Pharmacology, Xi’an Jiaotong University School of Medicine, Xi’an, China
| | - Xiaolu Zhang
- Department of Pharmacology, Xi’an Jiaotong University School of Medicine, Xi’an, China
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Deminice R, Silva TCV, Oliveira VHFD. Elevated homocysteine levels in human immunodeficiency virus-infected patients under antiretroviral therapy: A meta-analysis. World J Virol 2015; 4:147-155. [PMID: 25964880 PMCID: PMC4419119 DOI: 10.5501/wjv.v4.i2.147] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2014] [Revised: 11/28/2014] [Accepted: 03/05/2015] [Indexed: 02/05/2023] Open
Abstract
AIM: To evaluate the association between the levels of homocysteine (Hcy), folate, vitamin B12 in human immunodeficiency virus (HIV)-infected patients who were treated with antiretroviral therapy (ART) or not treated with ART.
METHODS: The PubMed and Scielo databases were searched. Eligible studies regarding plasma Hcy level in HIV-infected patients were firstly identified. After careful analysis by two independent researches, the identified articles were included in the review according to two outcomes (1) Hcy, folate and vitamin B12 blood concentration in HIV-infected subjects vs health controls and; (2) Hcy blood concentration in HIV-infected subjects under ART vs not treated with ART. RevMan (version 5.2) was employed for data synthesis.
RESULTS: A total of 12 studies were included in outcome 1 (1649 participants, 932 cases and 717 controls). Outcome 1 meta-analysis demonstrated higher plasma Hcy (2.05 µmol/L; 95%CI: 0.10 to 4.00, P < 0.01) and decreased plasma folate concentrations (-2.74 ng/mL; 95%CI: -5.18 to -0.29, P < 0.01) in HIV-infected patients compared to healthy controls. No changes in vitamin B12 plasma concentration were observed between groups. All studies included in the outcome 2 meta-analysis (1167 participants; 404 HIV-infected exposed to ART and 757 HIV-infected non-ART patients) demonstrated higher mean Hcy concentration in subjects HIV-infected under ART compared to non-ART HIV subjects (4.13 µmol/L; 95%CI: 1.34 to 6.92, P < 0.01).
CONCLUSION: This meta-analysis demonstrated that the levels of Hcy and folate, but not vitamin B12, were associated with HIV infection. In addition, Hcy levels were higher in HIV-infected patients who were under ART compared to HIV-infected patients who were not exposed to ART. Our results suggest that hyperhomocysteinemia should be included among the several important metabolic disturbances that are associated with ART in patients with HIV infection.
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Mindin regulates vascular smooth muscle cell phenotype and prevents neointima formation. Clin Sci (Lond) 2015; 129:129-45. [PMID: 25751394 DOI: 10.1042/cs20140679] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
In the present study, using diverse in vitro and in vivo models, we revealed that mindin is a novel modulator of VSMC phenotype and neointima formation in an AKT-dependent manner in response to vascular injury.
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Houston BA, Mukherjee M. Cardiac sarcoidosis: clinical manifestations, imaging characteristics, and therapeutic approach. CLINICAL MEDICINE INSIGHTS-CARDIOLOGY 2014; 8:31-7. [PMID: 25452702 PMCID: PMC4240214 DOI: 10.4137/cmc.s15713] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Revised: 10/12/2014] [Accepted: 10/21/2014] [Indexed: 12/26/2022]
Abstract
Sarcoidosis is a multi-system disease pathologically characterized by the accumulation of T-lymphocytes and mononuclear phagocytes into the sine qua non pathologic structure of the noncaseating granuloma. Cardiac involvement remains a key source of morbidity and mortality in sarcoidosis. Definitive diagnosis of cardiac sarcoidosis, particularly early enough in the disease course to provide maximal therapeutic impact, has proven a particularly difficult challenge. However, major advancements in imaging techniques have been made in the last decade. Advancements in imaging modalities including echocardiography, nuclear spectroscopy, positron emission tomography, and magnetic resonance imaging all have improved our ability to diagnose cardiac sarcoidosis, and in many cases to provide a more accurate prognosis and thus targeted therapy. Likewise, therapy for cardiac sarcoidosis is beginning to advance past a “steroids-only” approach, as novel immunosuppressant agents provide effective steroid-sparing options. The following focused review will provide a brief discussion of the epidemiology and clinical presentation of cardiac sarcoidosis followed by a discussion of up-to-date imaging modalities employed in its assessment and therapeutic approaches.
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Affiliation(s)
- Brian A Houston
- Division of Cardiology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA
| | - Monica Mukherjee
- Division of Cardiology, Department of Medicine, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA
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Hyperhomocysteinemia accelerates collagen accumulation in the adventitia of balloon-injured rat carotid arteries via angiotensin II type 1 receptor. Int J Mol Sci 2014; 15:19487-98. [PMID: 25350112 PMCID: PMC4264124 DOI: 10.3390/ijms151119487] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2014] [Revised: 08/25/2014] [Accepted: 09/28/2014] [Indexed: 01/21/2023] Open
Abstract
Recent studies suggest that hyperhomocysteinemia (HHcy) increases collagen type I accumulation in rat vascular adventitia after balloon injury and that Angiotensin II (Ang II) induces collagen synthesis in vascular adventitial fibroblasts. Reports also indicate that Ang II type1 receptor (AT1R) activation, mediated by homocysteine (Hcy) may contribute to collagen type 1 expression in mouse aortic endothelial cells. However, little is known about the possible mechanisms behind the relationship between Hcy and AT1R in adventitial remodeling. Thus, we investigated whether HHcy induces collagen accumulation via activation of AT1R in the adventitia. Male Sprague-Dawley (SD) rats were randomly divided into a control group and a 1% l-methionine-induced HHcy group. Balloon injury was performed after 12 experimental weeks and animals were sacrificed at 7, 14, and 28 days after injury. Collagen deposition and AT1R expression was measured with Western blot. Serum Hcy, adventitial collagen, and AT1R levels were higher in the HHcy group compared with the control group. Hcy time-dependently induced collagen type 1 and AT1R expression, with the highest induction observed at 48 h. Also, we observed that the AT1R blocker, valsartan, attenuated collagen type 1 and AT1R expression. HHcy exacerbates adventitial remodeling after balloon injury, and the underling mechanisms may be related to AT1R activity.
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Huang L, Zhang SM, Zhang P, Zhang XJ, Zhu LH, Chen K, Gao L, Zhang Y, Kong XJ, Tian S, Zhang XD, Li H. Interferon regulatory factor 7 protects against vascular smooth muscle cell proliferation and neointima formation. J Am Heart Assoc 2014; 3:e001309. [PMID: 25304854 PMCID: PMC4323813 DOI: 10.1161/jaha.114.001309] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Background Interferon regulatory factor 7 (IRF7), a member of the interferon regulatory factor family, plays important roles in innate immunity and immune cell differentiation. However, the role of IRF7 in neointima formation is currently unknown. Methods and Results Significant decreases in IRF7 expression were observed in vascular smooth muscle cells (VSMCs) following carotid artery injury in vivo and platelet‐derived growth factor‐BB (PDGF‐BB) stimulation in vitro. Compared with non‐transgenic (NTG) controls, SMC‐specific IRF7 transgenic (IRF7‐TG) mice displayed reduced neointima formation and VSMC proliferation in response to carotid injury, whereas a global knockout of IRF7 (IRF7‐KO) resulted in the opposite effect. Notably, a novel IRF7‐KO rat strain was successfully generated and used to further confirm the effects of IRF7 deletion on the acceleration of intimal hyperplasia based on a balloon injury‐induced vascular lesion model. Mechanistically, IRF7's inhibition of carotid thickening and the expression of VSMC proliferation markers was dependent on the interaction of IRF7 with activating transcription factor 3 (ATF3) and its downstream target, proliferating cell nuclear antigen (PCNA). The evidence that IRF7/ATF3‐double‐TG (DTG) and IRF7/ATF3‐double‐KO (DKO) mice abolished the regulatory effects exhibited by the IRF7‐TG and IRF7‐KO mice, respectively, validated the underlying molecular events of IRF7‐ATF3 interaction. Conclusions These findings demonstrated that IRF7 modulated VSMC proliferation and neointima formation by interacting with ATF3, thereby inhibiting the ATF3‐mediated induction of PCNA transcription. The results of this study indicate that IRF7 is a novel modulator of neointima formation and VSMC proliferation and may represent a promising target for vascular disease therapy.
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Affiliation(s)
- Ling Huang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (L.H., S.M.Z., P.Z., L.H.Z., Y.Z., X.J.K., S.T., H.L.) Cardiovascular Research Institute of Wuhan University, Wuhan, China (L.H., S.M.Z., P.Z., L.H.Z., Y.Z., X.J.K., S.T., H.L.)
| | - Shu-Min Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (L.H., S.M.Z., P.Z., L.H.Z., Y.Z., X.J.K., S.T., H.L.) Cardiovascular Research Institute of Wuhan University, Wuhan, China (L.H., S.M.Z., P.Z., L.H.Z., Y.Z., X.J.K., S.T., H.L.)
| | - Peng Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (L.H., S.M.Z., P.Z., L.H.Z., Y.Z., X.J.K., S.T., H.L.) Cardiovascular Research Institute of Wuhan University, Wuhan, China (L.H., S.M.Z., P.Z., L.H.Z., Y.Z., X.J.K., S.T., H.L.)
| | - Xiao-Jing Zhang
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, China (X.J.Z.)
| | - Li-Hua Zhu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (L.H., S.M.Z., P.Z., L.H.Z., Y.Z., X.J.K., S.T., H.L.) Cardiovascular Research Institute of Wuhan University, Wuhan, China (L.H., S.M.Z., P.Z., L.H.Z., Y.Z., X.J.K., S.T., H.L.)
| | - Ke Chen
- College of Life Sciences, Wuhan University, Wuhan, China (K.C., X.D.Z.)
| | - Lu Gao
- Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (L.G.)
| | - Yan Zhang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (L.H., S.M.Z., P.Z., L.H.Z., Y.Z., X.J.K., S.T., H.L.) Cardiovascular Research Institute of Wuhan University, Wuhan, China (L.H., S.M.Z., P.Z., L.H.Z., Y.Z., X.J.K., S.T., H.L.)
| | - Xiang-Jie Kong
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (L.H., S.M.Z., P.Z., L.H.Z., Y.Z., X.J.K., S.T., H.L.) Cardiovascular Research Institute of Wuhan University, Wuhan, China (L.H., S.M.Z., P.Z., L.H.Z., Y.Z., X.J.K., S.T., H.L.)
| | - Song Tian
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (L.H., S.M.Z., P.Z., L.H.Z., Y.Z., X.J.K., S.T., H.L.) Cardiovascular Research Institute of Wuhan University, Wuhan, China (L.H., S.M.Z., P.Z., L.H.Z., Y.Z., X.J.K., S.T., H.L.)
| | - Xiao-Dong Zhang
- College of Life Sciences, Wuhan University, Wuhan, China (K.C., X.D.Z.)
| | - Hongliang Li
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China (L.H., S.M.Z., P.Z., L.H.Z., Y.Z., X.J.K., S.T., H.L.) Cardiovascular Research Institute of Wuhan University, Wuhan, China (L.H., S.M.Z., P.Z., L.H.Z., Y.Z., X.J.K., S.T., H.L.)
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Zhao Y, Wu S, Gao X, Zhang Z, Gong J, Zhan R, Wang X, Wang W, Qian L. Inhibition of cystathionine β-synthase is associated with glucocorticoids over-secretion in psychological stress-induced hyperhomocystinemia rat liver. Cell Stress Chaperones 2013; 18:631-41. [PMID: 23512717 PMCID: PMC3745252 DOI: 10.1007/s12192-013-0416-0] [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: 11/06/2012] [Revised: 02/26/2013] [Accepted: 03/01/2013] [Indexed: 01/29/2023] Open
Abstract
Hyperhomocysteinemia (HHcy), a pathological condition characterized by an increase in plasma concentration of total homocysteine (Hcy), is recognized as a risk factor for several diseases. The transsulfuration pathway is the main metabolic fate of Hcy utilization, which requires the activity of cystathionine β-synthase (CBS). Our results showed the development of HHcy induced by psychological stress was mainly derived from a reduction of CBS activity in the liver, which was accompanied by a significant decrease in its mRNA level. It suggested that the hepatic CBS enzyme regulated by stress at the level of transcription would have a profound effect on circulating Hcy levels. The expression of Sp3, a negative factor for cbs transcription, obviously increased in hepatocytes nuclei of stressed rats, but Sp1 was not altered. It indicated that Sp3 was the key point of variations in cbs transcription caused by stress. Meanwhile, we detected that augmented plasma Hcy concentrations correlated with glucocordicoids (GCs) over-secretion in response to stress, and CBS mRNA levels were markedly lowered in GCs-treated rat hepatocytes. Further results found that glucocorticoids receptor (GR) expression in hepatocyte nuclei of stress rats and GR nuclear translocation ratio was increased, and the same results were proved by experiments in vitro, i.e., GR nuclear translocation and Sp3 expression was remarkably increased in GCs-treated hepatocytes. Moreover, results from ChIP suggested GCs enhanced the binding of GR to the regulatory region of the Sp3 promoter. These results indicated that GCs inhibit CBS transcription by up-regulating Sp3 in psychological stress-induced HHcy.
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Affiliation(s)
- Yun Zhao
- />Key laboratory of stress medicine, Institute of Basic Medical Sciences, Beijing, China
| | - Shuqing Wu
- />Key laboratory of stress medicine, Institute of Basic Medical Sciences, Beijing, China
| | - Xiujie Gao
- />Institute of Health and Environmental Medicine, Tianjin, China
| | - Zhiqing Zhang
- />Institute of Health and Environmental Medicine, Tianjin, China
| | - Jingbo Gong
- />Key laboratory of stress medicine, Institute of Basic Medical Sciences, Beijing, China
| | - Rui Zhan
- />Key laboratory of stress medicine, Institute of Basic Medical Sciences, Beijing, China
| | - Xinxing Wang
- />Key laboratory of stress medicine, Institute of Basic Medical Sciences, Beijing, China
| | - Weiming Wang
- />Beijing University of Chinese Medicine, Beijing, China
| | - Lingjia Qian
- />Key laboratory of stress medicine, Institute of Basic Medical Sciences, Beijing, China
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25
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Liu DS, Gao W, Liang ES, Wang SL, Lin WW, Zhang WD, Jia Q, Guo RC, Zhang JD. Effects of allicin on hyperhomocysteinemia-induced experimental vascular endothelial dysfunction. Eur J Pharmacol 2013; 714:163-9. [PMID: 23792140 DOI: 10.1016/j.ejphar.2013.05.038] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2012] [Revised: 05/17/2013] [Accepted: 05/30/2013] [Indexed: 01/01/2023]
Abstract
This study was designed to investigate the effect and mechanism of allicin on hyperhomocysteinemia-induced experimental vascular endothelial dysfunction in rats. Fifty male Wistar rats were randomly divided into five groups: the normal control rats (NC), the high-methionine-diet rats (Met), the high-methionine-diet rats treated with folic acid, vitaminB₆ and vitaminB₁₂ (Met+F), or with low-dose allicin (Met+L), or with high-dose allicin (Met+H). After 6 weeks, we collected blood samples of all groups to determine plasma endothelin (ET), serum homocysteine (Hcy), nitric oxide (NO), superoxide dismutase (SOD), malondialdehyde (MDA), and detected the expression of basic fibroblast growth factors (bFGF), transforming growth factor beta (TGF-β), tumor necrosis factor-alpha (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) in the aorta. The Hcy and the expression of TGF-β in both the Met+L and Met+H groups were significantly lower than the Met and Met+F groups. The ET, ET/NO ratio and the MDA levels of the Met+L and Met+H groups were significantly lower than the Met group. The SOD and NO levels and the expression of bFGF, TNF-α and ICAM-1 of the Met+L and Met+H groups were significantly higher than the Met group. Our data indicate that allicin inhibits lipid peroxidation induced by hyperhomocysteinemia and regulates the excretion and equilibrium of ET and NO, and suggest that allicin might be useful in the prevention of endothelial dysfunction caused by hyperhomocysteinemia.
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Affiliation(s)
- De-shan Liu
- Department of Traditional Chinese Medicine, Qilu Hospital of Shandong University, Jinan 250012, PR China.
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26
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Zhang D, Chen Y, Xie X, Liu J, Wang Q, Kong W, Zhu Y. Homocysteine activates vascular smooth muscle cells by DNA demethylation of platelet-derived growth factor in endothelial cells. J Mol Cell Cardiol 2012; 53:487-96. [PMID: 22867875 DOI: 10.1016/j.yjmcc.2012.07.010] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2012] [Revised: 07/18/2012] [Accepted: 07/19/2012] [Indexed: 02/05/2023]
Abstract
Hyperhomocysteinemia (HHcy), as an independent risk factor of atherosclerosis, facilitates endothelial dysfunction and activation of vascular smooth muscle cells (VSMCs). However, little is known about the crosstalk between endothelial cells (ECs) and VSMCs under HHcy. We investigated whether homocysteine (Hcy) activates VSMCs by aberrant secretion of mitogen platelet-derived growth factors (PDGFs) from ECs in human and in mice. In this study, we found that increased Hcy level did not affect VSMC activity in 24 hrs until the concentration reached 500 μM. In contrast, Hcy at 100 μM significantly promoted proliferation and migration of VSMCs co-cultured with human ECs. This effect was partially reversed by pretreatment with a PDGF receptor inhibitor. Hcy concentration-dependently upregulated the mRNA level of PDGF-A, -C and -D but not PDGF-B in ECs. Hcy reduced the expression and activity of DNA methyltransferase 1, demethylation of PDGF-A, -C and -D promoters and enhanced the binding activity of transcriptional factor SP-1 to the promoter. Hcy upregulation of PDGF was confirmed in the aortic intima of mice with HHcy. Multivariate regression analysis revealed HHcy was a predictor of increased serum PDGF level in patients. Thus, Hcy upregulates PDGF level via DNA demethylation in ECs, affects cross-talk between ECs and VSMCs and leads to VSMC activation.
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Affiliation(s)
- Donghong Zhang
- Cardiovascular Research Center, Shantou University Medical College, Shantou, Guangdong, 515041, China
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27
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Wang R. Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol Rev 2012; 92:791-896. [PMID: 22535897 DOI: 10.1152/physrev.00017.2011] [Citation(s) in RCA: 1419] [Impact Index Per Article: 109.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The important life-supporting role of hydrogen sulfide (H(2)S) has evolved from bacteria to plants, invertebrates, vertebrates, and finally to mammals. Over the centuries, however, H(2)S had only been known for its toxicity and environmental hazard. Physiological importance of H(2)S has been appreciated for about a decade. It started by the discovery of endogenous H(2)S production in mammalian cells and gained momentum by typifying this gasotransmitter with a variety of physiological functions. The H(2)S-catalyzing enzymes are differentially expressed in cardiovascular, neuronal, immune, renal, respiratory, gastrointestinal, reproductive, liver, and endocrine systems and affect the functions of these systems through the production of H(2)S. The physiological functions of H(2)S are mediated by different molecular targets, such as different ion channels and signaling proteins. Alternations of H(2)S metabolism lead to an array of pathological disturbances in the form of hypertension, atherosclerosis, heart failure, diabetes, cirrhosis, inflammation, sepsis, neurodegenerative disease, erectile dysfunction, and asthma, to name a few. Many new technologies have been developed to detect endogenous H(2)S production, and novel H(2)S-delivery compounds have been invented to aid therapeutic intervention of diseases related to abnormal H(2)S metabolism. While acknowledging the challenges ahead, research on H(2)S physiology and medicine is entering an exponential exploration era.
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Affiliation(s)
- Rui Wang
- Department of Biology, Lakehead University, Thunder Bay, Ontario, Canada.
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28
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Su TC, Torng PL, Jeng JS, Chen MF, Liau CS. Arterial function of carotid and brachial arteries in postmenopausal vegetarians. Vasc Health Risk Manag 2011; 7:517-23. [PMID: 21915169 PMCID: PMC3166191 DOI: 10.2147/vhrm.s18881] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2011] [Indexed: 12/27/2022] Open
Abstract
Background: Vegetarianism is associated with a lower risk of cardiovascular disease. However, studies of arterial function in vegetarians are limited. Methods: This study investigated arterial function in vegetarianism by comparing 49 healthy postmenopausal vegetarians with 41 age-matched omnivores. The arterial function of the common carotid artery was assessed by carotid duplex, while the pulse dynamics method was used to measure brachial artery distensibility (BAD), compliance (BAC), and resistance (BAR). Fasting blood levels of glucose, lipids, lipoprotein (a), high-sensitivity C-reactive protein, homocysteine, and vitamin B12 were also measured. Results: Vegetarians had significantly lower serum cholesterol, high-density and low-density lipoprotein, and glucose compared with omnivores. They also had lower vitamin B12 but higher homocysteine levels. Serum levels of lipoprotein (a) and high-sensitivity C-reactive protein were no different between the two groups. There were no significant differences in carotid beta stiffness index, BAC, and BAD between the two groups even after adjustment for associated covariates. However, BAR was significantly lower in vegetarians than in omnivores. Multiple linear regression analysis revealed that age and pulse pressure were two important determinants of carotid beta stiffness index and BAD. Vegetarianism is not associated with better arterial elasticity. Conclusion: Apparently healthy postmenopausal vegetarians are not significantly better in terms of carotid beta stiffness index, BAC, and BAD, but have significantly decreased BAR than omnivores. Prevention of vitamin B12 deficiency might be beneficial for cardiovascular health in vegetarians.
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Affiliation(s)
- Ta-Chen Su
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
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29
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Ciaccio M, Bivona G, Bellia C. Therapeutical approach to plasma homocysteine and cardiovascular risk reduction. Ther Clin Risk Manag 2011; 4:219-24. [PMID: 18728711 PMCID: PMC2503657 DOI: 10.2147/tcrm.s1807] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Homocysteine is a sulfur-containing aminoacid produced during metabolism of methionine. Since 1969 the relationship between altered homocysteine metabolism and both coronary and peripheral atherotrombosis is known; in recent years experimental evidences have shown that elevated plasma levels of homocysteine are associated with an increased risk of atherosclerosis and cardiovascular ischemic events. Several mechanisms by which elevated homocysteine impairs vascular function have been proposed, including impairment of endothelial function, production of reactive oxygen species (ROS) and consequent oxidation of low-density lipids. Endothelial function is altered in subjects with hyperhomocysteinemia, and endothelial dysfunction is correlated with plasma levels of homocysteine. Folic acid and B vitamins, required for remethylation of homocysteine to methionine, are the most important dietary determinants of homocysteine and daily supplementation typically lowers plasma homocysteine levels; it is still unclear whether the decreased plasma levels of homocysteine through diet or drugs may be paralleled by a reduction in cardiovascular risk.
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Affiliation(s)
- Marcello Ciaccio
- Department of Medical Biotechnologies and Forensic Medicine, Faculty of Medicine, University of Palermo Italy
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30
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Chen M, Wang Y, Zhao Y, Wang L, Gong J, Wu L, Gao X, Yang Z, Qian L. Dynamic proteomic and metabonomic analysis reveal dysfunction and subclinical injury in rat liver during restraint stress. BIOCHIMICA ET BIOPHYSICA ACTA-PROTEINS AND PROTEOMICS 2009; 1794:1751-65. [DOI: 10.1016/j.bbapap.2009.08.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2009] [Revised: 08/05/2009] [Accepted: 08/06/2009] [Indexed: 12/28/2022]
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Yu X, Ling W, Mi M. Relationship of impairment induced by intracellular S-adenosylhomocysteine accumulation with DNA methylation in human umbilical vein endothelial cells treated with 3-deazaadenosine. Int J Exp Pathol 2009; 90:638-48. [PMID: 19958400 PMCID: PMC2803255 DOI: 10.1111/j.1365-2613.2009.00687.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2008] [Accepted: 09/13/2008] [Indexed: 11/28/2022] Open
Abstract
The aim of this study was to estimate the relationship of endothelial dysfunction induced by intracellular S-adenosylhomocysteine (SAH) accumulation and DNA methylation in human umbilical vein endothelial cells (HUVEC). The isolated HUVEC were incubated with 3-deazaadenosine (DZA) to induce experimental intracellular SAH accumulation. The impairment of HUVEC function was assessed by changes in morphology and proliferative ability. The expression of DNA methyltransferase-1 (DNMT1) and the atherosclerosis related genes [oestrogen receptor-alpha (ER-alpha), extracellular superoxide dismutase (EC-SOD) and monocyte chemoattractant protein-1 (MCP-1)] were analysed using quantitative real-time PCR. Global DNA methylated status was measured using the cytosine extension assay. The methylated patterns of ER-alpha, EC-SOD and MCP-1 genes were determined with methylation-specific PCR. We found that DZA administration increased intracellular SAH levels progressively and simultaneously decreased Hcy content in medium. Moreover, the supplementation induced HUVEC apoptosis, inhibited proliferation ability and DNMT1 mRNA expression (P < 0.05) and furthermore reduced global DNA methylation status (P < 0.05). Correlation analysis showed the presence of a negative correlation between intracellular SAH concentration, proliferative ability, and expression of ER-alpha, EC-SOD, and DNMT1 (r = -0.89, -0.86, -0.92 and -0.88 respectively, P < 0.001); and a positive correlation with MCP-1 expression and DNA [(3)H]-dCTP incorporation (r = 0.89 and 0.93 respectively, P < 0.001). Our results showed that endothelial dysfunction induced by intracellular SAH accumulation is mediated by regulating the expression of atherosclerosis related genes in HUVEC, which is not related with gene promoter methylated patterns, but may be associated with altered global DNA hypomethylated status. These findings suggest that SAH can act as the potential molecular biological marker in the promotion of atherogenesis.
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Affiliation(s)
- Xiaoping Yu
- Department of Public Health, School of Preclinical Medicine, Chengdu Medical CollegeChengdu, Sichuan, China
- Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus)Guangzhou, China
- Department of Nutrition and Food Hygiene, School of Preventive Medicine, The Third Military Medical UniversityShapingba District, Chongqing, China
| | - Wenhua Ling
- Department of Nutrition, School of Public Health, Sun Yat-sen University (Northern Campus)Guangzhou, China
| | - Mantian Mi
- Department of Nutrition and Food Hygiene, School of Preventive Medicine, The Third Military Medical UniversityShapingba District, Chongqing, China
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32
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Diet-induced hyperhomocysteinemia exacerbates vascular reverse remodeling of balloon-injured arteries in rat. Chin Med J (Engl) 2008. [DOI: 10.1097/00029330-200811020-00011] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
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Wang JH, Subeq YM, Tsai WC, Lee RP, Hsu BG. Intravenous N-acetylcysteine with saline hydration improves renal function and ameliorates plasma total homocysteine in patients undergoing cardiac angiography. Ren Fail 2008; 30:527-33. [PMID: 18569934 DOI: 10.1080/08860220802064754] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
Abstract
Proinflammatory cytokines and hyperhomocysteinemia are associated with clinically relevant restenosis in coronary artery disease. N-acetylcysteine (NAC) can decrease proinflammatory cytokines and plasma homocystine as well as reduce contrast-induced nephropathy. The aim of this study, therefore, was to compare normal saline hydration with and without intravenous NAC in terms of changes in renal function, proinflammatory cytokines, inflammatory markers, and plasma total homocysteine during coronary angiography. Forty-six patients who underwent coronary angiography and/or stent implantation for unstable angina were enrolled and assigned to NAC or NS treatment groups based on normal saline hydration with or without intravenous NAC, respectively. The NS group had lower serum creatinine (Cre: p = 0.02) and plasma total homocysteine (tHcy; p < 0.001) and increased glomerular filtration rate (GFR; p = 0.003) after angiography. In the NAC group, the serum blood urea nitrogen (BUN; p = 0.001), Cre (p < 0.001), and plasma tHcy (p < 0.001) were lower, and the GFR (P = 0.013) was increased after angiography. There were no statistically significant differences in serum high-sensitivity C reactive protein (hs-CRP), tumor necrosis factor-alpha (TNF-alpha), or interleukin-10 (IL-10) before and after angiography in the NS and NAC groups. Intergroup comparison revealed that plasma tHcy level was lower for the NAC-treated patients (p = 0.002), with lower plasma tHcy level before and after treatment in this group (p < 0.001). Normal saline hydration can improve renal function and decrease plasma tHcy after coronary angiography with or without NAC; however, the combination of the two decreases plasma tHcy more than normal saline hydration alone.
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Affiliation(s)
- Ji-Hung Wang
- Department of Cardiology, Buddhist Tzu Chi General Hospital, Hualien, Taiwan
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Liu F, Zhang J, Yu S, Wang R, Wang B, Lai L, Yin H, Liu G. Inhibitory effect of Ginkgo biloba extract on hyperhomocysteinemia-induced intimal thickening in rabbit abdominal aorta after balloon injury. Phytother Res 2008; 22:506-10. [PMID: 18167042 DOI: 10.1002/ptr.2353] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Ginkgo biloba extract (GBE) has been widely used to treat cardiovascular and cerebrovascular disorders. Hyperhomocysteinemia (Hhcy) is associated with the risk of atherosclerosis and restenosis after angioplasty. The objective of this study was to investigate whether GBE could attenuate the Hhcy-induced intimal thickening after balloon injury in rabbit abdominal aorta. It was observed in this study that GBE could decrease the neointima area (NA) and the ratio of the neointima area to the media area (NA/MA), down-regulate the mRNA expression of matrix metalloproteinase-9 (MMP-9) and up-regulate the protein expression of p21 (WAF1/CIP1) (p21). It suggests that GBE can reverse the Hhcy-induced neointima formation in rabbits following balloon injury, and the suppressive effect of GBE on the migration and proliferation of vascular smooth muscle cells (VSMCs) may contribute to its actions.
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Affiliation(s)
- Fenye Liu
- Department of Traditional Chinese Medicine, Qilu Hospital Affiliated to Shandong University, Jinan 250012, Shandong, PR China
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35
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Dayal S, Lentz SR. Murine models of hyperhomocysteinemia and their vascular phenotypes. Arterioscler Thromb Vasc Biol 2008; 28:1596-605. [PMID: 18556571 DOI: 10.1161/atvbaha.108.166421] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Hyperhomocysteinemia is an established risk factor for arterial as well as venous thromboembolism. Individuals with severe hyperhomocysteinemia caused by inherited genetic defects in homocysteine metabolism have an extremely high incidence of vascular thrombosis unless they are treated aggressively with homocysteine-lowering therapy. The clinical value of homocysteine-lowering therapy in individuals with moderate hyperhomocysteinemia, which is very common in populations at risk for vascular disease, is more controversial. Considerable progress in our understanding of the molecular mechanisms underlying the association between hyperhomocysteinemia and vascular thrombotic events has been provided by the development of a variety of murine models. Because levels of homocysteine are regulated by both the methionine and folate cycles, hyperhomocysteinemia can be induced in mice through both genetic and dietary manipulations. Mice deficient in the cystathionine beta-synthase (CBS) gene have been exploited widely in many studies investigating the vascular pathophysiology of hyperhomocysteinemia. In this article, we review the established murine models, including the CBS-deficient mouse as well as several newer murine models available for the study of hyperhomocysteinemia. We also summarize the major vascular phenotypes observed in these murine models.
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Affiliation(s)
- Sanjana Dayal
- Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, USA
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Effects of moderate hyperhomocysteinaemia induced by 4 weeks methionine-enriched diet on metabolite profile and mesenteric artery function in rats. Br J Nutr 2008; 99:993-9. [DOI: 10.1017/s0007114508853408] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Methionine is an essential amino acid and methyl donor for most transmethylation reactions in mammals. The product of transmethylation reactions is homocysteine, which is associated with enhanced risk for CVD. The aim of this study was to analyse metabolic and vascular functional consequences of a methionine-enriched diet in rats. The dose of methionine was chosen to reflect the range of over-nutrition in man. We quantified plasma levels of homocysteine, asymmetrical dimethylarginine and adenosine, determined methionine and its metabolites in tissues and blood plasma and assessed relaxation of mesenteric arteries toward acetylcholine and sodium nitroprusside. A methionine-enriched diet for 4 weeks elevated homocysteine levels in plasma 2-fold and in spleen by 70 %. The level of S-adenosylhomocysteine was increased in liver only, while methionine and S-adenosylmethionine were unchanged in all organs studied. Plasma adenosine and asymmetrical dimethylarginine levels were unchanged, as were vessel relaxations. A 2-fold elevation of plasma homocysteine, which is assigned a risk indicator for cardiovascular events, did not impair mesenteric artery vasodilatation during 4 weeks of a methionine-rich diet. Furthermore, asymmetrical dimethylarginine and adenosine, which have been shown to be changed in more severe degrees of hyperhomocysteinaemia, remained unaltered.
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Distrutti E, Mencarelli A, Santucci L, Renga B, Orlandi S, Donini A, Shah V, Fiorucci S. The methionine connection: homocysteine and hydrogen sulfide exert opposite effects on hepatic microcirculation in rats. Hepatology 2008; 47:659-67. [PMID: 18098324 DOI: 10.1002/hep.22037] [Citation(s) in RCA: 55] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
UNLABELLED Increased intrahepatic resistance in cirrhotic livers is caused by endothelial dysfunction and impaired formation of two gaseous vasodilators, nitric oxide (NO) and hydrogen sulfide (H(2)S). Homocysteine, a sulfur-containing amino acid and H(2)S precursor, is formed from hepatic methionine metabolism. In the systemic circulation, hyperhomocystenemia impairs vasodilation and NO production from endothelial cells. Increased blood levels of homocysteine are common in patients with liver cirrhosis. In this study, we demonstrate that acute liver perfusion with homocysteine impairs NO formation and intrahepatic vascular relaxation induced by acetylcholine in methoxamine-precontracted normal livers (7.3% +/- 3.0% versus 26% +/- 2.7%; P < 0.0001). In rats with mild, diet-induced hyperhomocystenemia, the vasodilating activity of acetylcholine was markedly attenuated, and incremental increases in flow induced a greater percentage of increases in perfusion pressure than in control livers. Compared with normal rats, animals rendered cirrhotic by 12 weeks' administration of carbon tetrachloride exhibited a greater percentage of increments in perfusion pressure in response to shear stress (P < 0.05), and intrahepatic resistance to incremental increases in flow was further enhanced by homocysteine (P < 0.05). In normal hyperhomocysteinemic and cirrhotic rat livers, endothelial dysfunction caused by homocysteine was reversed by perfusion of the livers with sodium sulfide. Homocysteine reduced NO release from sinusoidal endothelial cells and also caused hepatic stellate cell contraction; this suggests a dual mechanism of action, with the latter effect being counteracted by H(2)S. CONCLUSION Impaired vasodilation and hepatic stellate cell contraction caused by homocysteine contribute to the dynamic component of portal hypertension.
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Affiliation(s)
- Eleonora Distrutti
- Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Perugia, Perugia, Italy
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Effect of folate on neointima formation and matrix metalloproteinase-9 expression after balloon injury in hyperhomocysteinemic rabbits. Int J Cardiol 2008; 131:59-65. [PMID: 18180053 DOI: 10.1016/j.ijcard.2007.08.138] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2007] [Revised: 08/09/2007] [Accepted: 08/18/2007] [Indexed: 11/23/2022]
Abstract
BACKGROUND It is known that hyperhomocysteinemia (Hhcy) is associated with the risk of restenosis after angioplasty. Folate can lower plasma homocysteine (Hcy) level and alleviate the Hhcy-induced neointima formation after balloon injury. This study aims to explore the mechanisms of folate in inhibiting neointima formation. METHODS 24 New Zealand White rabbits were randomly divided into three groups: Control, 2% methionine (Meth) and 2% methionine+folate (Meth+folate). At the end of 8 experimental weeks, all rabbits underwent the balloon injury in abdominal aorta. 4 weeks following this procedure, plasma Hcy concentration, aortic maximal neointimal thickness (NT), neointimal area (NA), medial area (MA), and ratio of neointimal area to medial area (NA/MA), ultrastructure of vascular smooth muscle cells (VSMCs), and matrix metalloproteinase-9 (MMP-9) expression were detected by high performance liquid chromatography, histomorphometric analysis, transmission electron microscope (TEM) and real-time PCR, respectively. RESULTS It was observed in our study that Hcy concentration, NT, NA, NA/MA and the expression of MMP-9 mRNA were higher in the Meth group than in the control. VSMCs in media exhibited typical synthetic phenotype in the Meth group compared with the transitional state between contractile phenotype and synthetic phenotype in the control group. However, in the rabbits treated with folate, Hcy concentration, NT, NA and MMP-9 mRNA expression were lower than those in the Meth group. The phenotype of VSMCs was close to that in the control group. CONCLUSION This study suggested that folate could decrease the level of Hcy, reverse the Hhcy-induced exacerbation of neointima formation in rabbits following balloon injury, and the mechanisms in it may be related to the suppressive effect of folate on the expression of MMP-9 mRNA in arterial wall.
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Abstract
Hyperhomocysteinemia is a risk factor for cardiovascular disease, stroke, and thrombosis. Several animal models of hyperhomocysteinemia have been developed by using both dietary and genetic approaches. These animal models have provided considerable insight into the mechanisms underlying the adverse vascular effects of hyperhomocysteinemia. Accumulating evidence suggests a significant role of altered cellular redox reactions in the vascular phenotype of hyperhomocysteinemia. Redox effects of hyperhomocysteinemia are particularly important in mediating the adverse effects of hyperhomocysteinemia on the endothelium, leading to loss of endothelium-derived nitric oxide and vasomotor dysfunction. Redox reactions also may be key factors in the development of vascular hypertrophy, thrombosis, and atherosclerosis in hyperhomocysteinemic animals. In this review, we summarize the metabolic relations between homocysteine and the cellular redox state, the vascular phenotypes that have been observed in hyperhomocysteinemic animals, the evidence for altered redox reactions in vascular tissue, and the specific redox reactions that may mediate the vascular effects of hyperhomocysteinemia.
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Affiliation(s)
- Sanjana Dayal
- Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa
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Meng QH, Yang G, Yang W, Jiang B, Wu L, Wang R. Protective effect of hydrogen sulfide on balloon injury-induced neointima hyperplasia in rat carotid arteries. THE AMERICAN JOURNAL OF PATHOLOGY 2007; 170:1406-14. [PMID: 17392179 PMCID: PMC1829473 DOI: 10.2353/ajpath.2007.060939] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Endogenous hydrogen sulfide (H(2)S), generated from homocysteine metabolism mainly catalyzed by cystathionine gamma-lyase (CSE), possesses important functions in the cardiovascular system. In this study, we investigated the role of H(2)S during the pathogenesis of neointimal formation induced by balloon injury in rats. CSE mRNA levels were reduced by 86.5% at 1 week and 64.0% at 4 weeks after balloon injury compared with the uninjured controls. CSE activity was also correspondingly reduced. Endogenous production of H(2)S in the injured carotid artery was significantly inhibited at 1 week and 4 weeks after balloon injury. Treatment with NaHS (a donor of H(2)S) enhanced methacholine-induced vasorelaxation of balloon-injured artery. More importantly, treatment with NaHS significantly inhibited neointima formation (0.15 +/- 0.01 mm(2) versus 0.21 +/- 0.01 mm(2), P < 0.001) of the balloon-injured carotid arteries and reduced the intima/media ratio (1.05 +/- 0.07 versus 1.43 +/- 0.06, P < 0.001). A significant decrease in vascular smooth muscle cell proliferation was demonstrated by bromodeoxyuridine incorporation at day 7 after injury. In conclusion, CSE expression and H(2)S production are reduced during the development of balloon injury-induced neointimal hyperplasia, and treatment with NaHS significantly reduces neointimal lesion formation.
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Affiliation(s)
- Qing H Meng
- Department of Pathology and Laboratory Medicine, University of Saskatchewan, 103 Hospital Drive, Saskatoon, SK, Canada S7N 0W8.
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Díez N, Pérez R, Hurtado V, Santidrián S. Hyperhomocysteinaemia induced by dietary folate restriction causes kidney oxidative stress in rats. Br J Nutr 2007; 94:204-10. [PMID: 16115354 DOI: 10.1079/bjn20051468] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Diet is the most common cause of mild hyperhomocysteinaemia (HHcy), which occurs in approximately 5–7 % of the general population. Since HHcy causes endothelial damage by oxidative stress in different organs, the present study was designed to examine whether HHcy might be involved in renal oxidative stress. Twenty-five male Wistar rats were randomly divided into two groups: one (n13) was fedad libituma folate-free diet (FF) and the other (n12) was fed the same diet supplemented with folic acid (control, CO). After 8 weeks the animals were killed and kidneys removed. Malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities were measured in plasma and kidney homogenates. Renal tissue sections were analysed by indirect immunostaining with the primary antibody against oxidatively modified LDL receptor (LOX-1). A marked HHcy was confirmed in the FF group. As compared with CO animals, MDA levels in plasma and kidney homogenate were significantly higher in FF rats (P<0·05). Similarly, renal GPx and SOD activities were significantly higher in the FF group (P<0·001). No differences were found in LOX-1 immunohistochemical expression, which in the two groups was displayed in tubular cells. The present study provides evidence that HHcy does produce renal oxidative stress mediated by lipid peroxidation, and that the increased kidney MDA displayed by FF animals may enhance kidney antioxidant activity and thereby attenuate both kidney damage and expression of LOX-1.
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Affiliation(s)
- Nieves Díez
- Department of Human Physiology, School of Medicine, University of Navarra, 31080 Pamplona, Spain
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Sayar N, Terzi S, Bilsel T, Yilmaz HY, Orhan L, Cakmak N, Erdem I, Tangurek B, Ciloglu F, Peker I, Yesilcimen K. Plasma homocysteine concentration in patients with poor or good coronary collaterals. Circ J 2007; 71:266-70. [PMID: 17251679 DOI: 10.1253/circj.71.266] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Elevated plasma homocysteine (Hcy) concentrations are associated with an increased risk of vascular disease. Hcy is known to inhibit endothelial cell proliferation in vitro. The purpose of the present study was to investigate the role of plasma Hcy concentrations on development of collateral circulation in single-vessel chronic total occlusion. METHODS AND RESULTS Collateral status was determined by Rentrop's classification. Of 817 patients, 56 cases of pure single-vessel chronic total occlusion were studied. Plasma Hcy concentrations in patients with single-vessel total coronary occlusion were higher compared with controls (17.3 +/-12.6 micromol/L vs 10.9+/-4.9 micromol/L, p=0.015). There was no significant difference in plasma Hcy concentrations of the good and poor collateral groups (17.2+/-13.7 micromol/L vs 15.3+/-9.3 micromol/L, p=0.834). Plasma Hcy concentrations in individual Rentrop subclasses 0, 1, 2 and 3 were as follows: 15.9 +/-9.1, 16.3+/-12.4, 17.1+/-14.1 and 20.1+/-13.5 micromol/L (p=0.893). There was a positive linear correlation between Rentrop subclass and angina pectoris duration (r=0.41, p=0.003). Angina pectoris duration was the only independent variable affecting the development of coronary collaterals in the present study (odds ratio [confidence interval]: 1.85 [1.12-2.91], p=0.014). CONCLUSION Patients with single-vessel chronic total occlusion had higher plasma Hcy concentrations than controls, but similar Hcy concentrations when compared according to the presence of poor or good coronary collaterals. There is a lack of association between plasma Hcy concentration and coronary collateral status in the current study.
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Affiliation(s)
- Nurten Sayar
- Siyami Ersek Cardiovascular and Thoracic Surgery Research Hospital, Department of Cardiology, Istanbul, Turkey.
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Hong M, Park S, Lee CW, Choi S, Song J, Kang D, Song J, Kim J, Park S. Elevated homocysteine levels might be associated with coronary artery remodeling in patients with stable angina: an intravascular ultrasound study. Clin Cardiol 2006; 25:225-9. [PMID: 12019514 PMCID: PMC6654071 DOI: 10.1002/clc.4950250506] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND The relationship between plasma biologic markers and coronary artery remodeling is unknown. HYPOTHESIS Plasma biologic markers are associated with coronary artery remodeling. METHODS Preintervention intravascular ultrasound images were obtained in 44 patients with chronic stable angina. Plasma samples were collected 24 h before coronary intervention. The biologic markers included total cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol, lipoprotein(a) [LP(a)], C-reactive protein (CRP), and homocysteine. The remodeling index (RI) was defined as a ratio of the (lesion/proximal reference) external elastic membrane cross-sectional area. Positive remodeling was defined as an RI > 1.05, negative remodeling as an RI <0.95, and intermediate remodeling as an RI between 0.95 and 1.05. RESULTS Total cholesterol level (r = 0.092, p = 0.557), LDL cholesterol level (r = 0.123, p = 0.426), triglyceride level (r = 0.020, p = 0.901), HDL cholesterol level (r = 0.042, p = 0.789), LP(a) level (r = 0.062, p = 0.729), and CRP level (r = 0.266, p = 0.089) did not significantly correlate with the RI. However, the plasma homocysteine level positively correlated with the RI (r = 0.398, p = 0.008). The plasma homocysteine level was significantly lower in the lesions with negative remodeling and higher in the lesions with positive remodeling (10.8 +/- 0.7 micromol/l in negative remodeling, 13.1 +/- 0.6 micromol/l in intermediate remodeling, and 18.1 +/- 2.8 micromol/l in positive remodeling, p = 0.021). CONCLUSIONS Elevated homocysteine levels might be associated with coronary artery remodeling in patients with stable angina.
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Affiliation(s)
- Myeong‐Ki Hong
- Department of Medicine, University of Ulsan College of Medicine, Cardiac Center, Asan Medical Center, Seoul, Korea
| | - Seong‐Wook Park
- Department of Medicine, University of Ulsan College of Medicine, Cardiac Center, Asan Medical Center, Seoul, Korea
| | - Cheol Whan Lee
- Department of Medicine, University of Ulsan College of Medicine, Cardiac Center, Asan Medical Center, Seoul, Korea
| | - Si‐Wan Choi
- Department of Medicine, University of Ulsan College of Medicine, Cardiac Center, Asan Medical Center, Seoul, Korea
| | - Jong‐Min Song
- Department of Medicine, University of Ulsan College of Medicine, Cardiac Center, Asan Medical Center, Seoul, Korea
| | - Duk‐Hyun Kang
- Department of Medicine, University of Ulsan College of Medicine, Cardiac Center, Asan Medical Center, Seoul, Korea
| | - Jae‐Kwan Song
- Department of Medicine, University of Ulsan College of Medicine, Cardiac Center, Asan Medical Center, Seoul, Korea
| | - Jae‐Joong Kim
- Department of Medicine, University of Ulsan College of Medicine, Cardiac Center, Asan Medical Center, Seoul, Korea
| | - Seung‐Jung Park
- Department of Medicine, University of Ulsan College of Medicine, Cardiac Center, Asan Medical Center, Seoul, Korea
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Bleys J, Miller ER, Pastor-Barriuso R, Appel LJ, Guallar E. Vitamin-mineral supplementation and the progression of atherosclerosis: a meta-analysis of randomized controlled trials. Am J Clin Nutr 2006; 84:880-7; quiz 954-5. [PMID: 17023716 DOI: 10.1093/ajcn/84.4.880] [Citation(s) in RCA: 116] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Laboratory and observational studies suggest that antioxidant and B vitamin supplementation may prevent atherosclerosis. Although trials have not shown a benefit of these supplements on clinical cardiovascular events, it is unknown whether they affect the progression of atherosclerosis as measured by imaging techniques. OBJECTIVE The objective was to perform a meta-analysis of randomized controlled trials of the effect of vitamin-mineral supplementation on atherosclerosis progression. DESIGN We searched the MEDLINE, EMBASE, and CENTRAL databases for relevant studies. No language restrictions were applied. We separately analyzed trials using antioxidants (vitamins E and C, beta-carotene, or selenium) and trials using B vitamins (folate, vitamin B-6, or vitamin B-12). The progression of atherosclerosis was evaluated by B-mode ultrasound, intravascular ultrasound, or angiography. Effect sizes were calculated for the difference in slope of atherosclerosis progression between participants assigned to supplements and those assigned to the control group. RESULTS In trials not involving percutaneous transluminal coronary angioplasty, the pooled effect size was -0.06 (95% CI: -0.20, 0.09; 7 trials) for antioxidants and -0.93 (95% CI: -2.11, 0.26; 4 trials) for B vitamins. In trials involving percutaneous transluminal coronary angioplasty, the pooled relative risk of restenosis was 0.82 (95% CI: 0.54, 1.26; 3 trials) for antioxidants and 0.84 (95% CI: 0.34, 2.07; 2 trials) for B vitamins. CONCLUSION Our meta-analysis showed no evidence of a protective effect of antioxidant or B vitamin supplements on the progression of atherosclerosis, thus providing a mechanistic explanation for their lack of effect on clinical cardiovascular events.
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Affiliation(s)
- Joachim Bleys
- Department of Epidemiology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA
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Kaul S, Zadeh AA, Shah PK. Homocysteine Hypothesis for Atherothrombotic Cardiovascular Disease. J Am Coll Cardiol 2006; 48:914-23. [PMID: 16949480 DOI: 10.1016/j.jacc.2006.04.086] [Citation(s) in RCA: 101] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2006] [Revised: 03/28/2006] [Accepted: 04/04/2006] [Indexed: 10/24/2022]
Abstract
Homocysteine has been implicated in promoting atherosclerotic and thrombotic vascular disease. During the last decade, the utility of homocysteine in predicting risk for atherothrombotic vascular disease has been evaluated in several observational studies in a large number of patients. These studies show that the overall risk for vascular disease is small, with prospective, longitudinal studies reporting a weaker association between homocysteine and atherothrombotic vascular disease compared to retrospective case-control and cross-sectional studies. Furthermore, randomized controlled trials of homocysteine-lowering therapy have failed to prove a causal relationship. On the basis of these results, there is currently insufficient evidence to recommend routine screening and treatment of elevated homocysteine concentrations with folic acid and other vitamins to prevent atherothrombotic vascular disease. This review outlines the metabolism and pathophysiology of homocysteine, highlights the results of homocysteine observational and interventional trials, and presents areas of uncertainty and potential future work.
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Affiliation(s)
- Sanjay Kaul
- Division of Cardiology, Cedars-Sinai Medical Center, University of California, Los Angeles, California 90048, USA.
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Shinohara Y, Hasegawa H, Ogawa K, Tagoku K, Hashimoto T. Distinct effects of folate and choline deficiency on plasma kinetics of methionine and homocysteine in rats. Metabolism 2006; 55:899-906. [PMID: 16784961 DOI: 10.1016/j.metabol.2006.02.017] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2005] [Accepted: 02/21/2006] [Indexed: 01/25/2023]
Abstract
Both folate and betaine, a choline metabolite, play essential roles in the remethylation of homocysteine to methionine. We have studied the effects of folate and choline deficiency on the plasma kinetics of methionine, especially remethylation of homocysteine to methionine, by means of stable isotope methodology. After a bolus intravenous administration of [(2)H(7)]methionine (5 mg/kg body weight) into the rats fed with folate-, choline-, folate + choline-deficient or control diets, the plasma concentrations of [(2)H(7)]methionine, demethylated [(2)H(4)]homocysteine, and remethylated [(2)H(4)]methionine were determined simultaneously with endogenous methionine and homocysteine by gas chromatography-mass spectrometry-selected ion monitoring. The total plasma clearance of [(2)H(7)]methionine was not significantly different among groups, suggesting that the formation of [(2)H(4)]homocysteine from [(2)H(7)]methionine was not influenced by deficiencies of folate and choline. The area under concentration-time curve of [(2)H(4)]homocysteine significantly increased in the folate- and folate + choline-deficient group as compared with the control, but not in the choline-deficient group. The time profile of plasma concentrations of [(2)H(4)]methionine in the folate-deficient group was the same as the control group, whereas the appearance of [(2)H(4)]methionine in plasma was delayed in the choline- and folate + choline-deficient group. These results suggested plasma levels of remethylated methionine were influenced by choline deficiency rather than folate deficiency.
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Affiliation(s)
- Yoshihiko Shinohara
- Department of Pathophysiology, School of Pharmacy, Tokyo University of Pharmacy and Life Science, Hachioji, Tokyo 192-0392, Japan.
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Zhu J, Wang X, Chen J, Sun J, Zhang F. Reduced number and activity of circulating endothelial progenitor cells from patients with hyperhomocysteinemia. Arch Med Res 2006; 37:484-9. [PMID: 16624647 DOI: 10.1016/j.arcmed.2005.09.017] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2005] [Accepted: 09/30/2005] [Indexed: 10/24/2022]
Abstract
BACKGROUND Hyperhomocysteinemia (HHcy) contributes to atherosclerosis and coronary artery diseases by inducing endothelial cell injury and dysfunction. Recent studies provided increasing evidence that endothelial progenitor cells (EPCs) participated in ongoing endothelial repair. The changes of EPCs in patients with HHcy have not yet been elucidated. Therefore, we investigated the number and functional activity of EPCs in patients with HHcy. METHODS Human EPCs were isolated and cultured from patients with HHcy (n = 30) and matched volunteers (n = 30). Circulating EPCs were enumerated as AC133+ KDR+ cells via fluorescence-activated cell sorter analysis. Additionally, EPC were expanded from human blood in vitro and identified by DiI-acLDL uptake and lectin staining by direct fluorescent staining under a laser scanning confocal microscope. EPC migration activities were determined by modified Boyden chamber assay. EPC adhesion assay was performed by replating cells on fibronectin-coated dishes and then counting adherent cells. RESULTS A significant decrease was observed in circulating EPC (AC133+ KDR+ cells) numbers in patients with HHcy compared with control subjects (63.9 +/- 11.7 cells/mL vs. 91.5 +/- 14.2 cells/mL blood, p <0.01). In addition, the numbers of EPCs also decreased in patients with HHcy after ex vivo cultivation (36.1 +/- 6.5 vs. 51.5 +/- 8.3 EPCs/x200 field, p <0.01). Both circulating EPCs and differentiated EPCs were inversely correlated with total homocysteine levels. In addition, EPCs from patients with HHcy were significantly impaired in their migratory capacity and ability to adhere to fibronectin compared with controls. CONCLUSIONS The present study demonstrated that EPC numbers and functional capacity were impaired in patients with HHcy.
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Affiliation(s)
- JunHui Zhu
- Department of Cardiology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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Ohashi R, Yan S, Mu H, Chai H, Yao Q, Lin PH, Chen C. Effects of Homocysteine and Ginsenoside Rb1 on Endothelial Proliferation and Superoxide Anion Production. J Surg Res 2006; 133:89-94. [PMID: 16271366 DOI: 10.1016/j.jss.2005.09.016] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2005] [Revised: 08/25/2005] [Accepted: 09/20/2005] [Indexed: 11/17/2022]
Abstract
BACKGROUND Homocysteine (Hcy) is an independent risk factor for cardiovascular disease by its multiple effects on vascular cells and throbmosis factors, which may be involved in oxidative stress mechansims. Ginsenoside Rb1, a constituent of ginseng, bears various beneficial effects on the cardiovascular system. In the present study, we investigated the effect of Hcy on endothelial proliferation and a protective effect of ginsenoside Rb1 on the action of Hcy. METHODS We initially incubated a mouse lymph node endothelial cell line (SVEC4-10) with increasing concentrations of Hcy or for different time periods and then assessed cell proliferation by using [(3)H]-thymidine incorporation. We then incubated SVEC4-10 cells with Hcy (50 microM) for 24 h with or without Rb1 (10 microM) to examine its inhibitory effect on the proliferation. These experiments were repeated in human umbilical vein endothelial cells (HUVECs). To explore the underlying molecular mechanisms, we measured superoxide anion, a reactive oxygen species (ROS), by using dihydroethidium (DHE) staining. RESULTS SVEC4-10 cells treated with Hcy (50, 100, and 200 microM) for 24 h significantly reduced cell proliferation by 43%, 42%, and 40%, respectively, as compared with control cells (P < 0.01). SVEC4-10 cells treated with Hcy (50 microM) for 12 and 24 h showed a significant reduction of cell proliferation (P < 0.05). In HUVECs, Hcy (50 microM) significantly reduced cell proliferation by 55% as compared with control cells (P < 0.05). In the presence of Rb1, Hcy-induced inhibition of cell proliferation was effectively blocked in both SVEC4-10 and HUVECs. Furthermore, Hcy (50 microM) significantly increased superoxide anion production by 23% in SVEC4-10 as compared with control cells (P < 0.05). However, in the presence of Rb1, Hcy increased superoxide anion production by only 8%, showing that RB1 almost completely blocked the effect of Hcy. CONCLUSION Hcy significantly inhibits endothelial proliferation with increased production of superoxide anion, which is effectively blocked by ginsenoside Rb1. This study provides some new aspects of Hcy-induced endothelial dysfunction, and suggests a potential role of Rb1 to block Hcy action, which may have clinical applications.
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Affiliation(s)
- Ryuji Ohashi
- Division of Vascular Surgery and Endovascular Therapy, Michael E. DeBakey Department of Surgery, Molecular Surgeon Research Center, Baylor College of Medicine, Houston, Texas 77030, USA
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Abstract
Homocysteine is a sulfur amino acid whose metabolism stands at the intersection of 2 pathways: remethylation, which requires folic acid and B-12 coenzymes, and transsulfuration, which requires pyridoxal-5'-phosphate, the B-6 coenzyme. Data from several studies suggest that mild elevations of homocysteine in plasma are a risk factor for occlusive vascular disease. In the Framingham studies we have shown that plasma total homocysteine concentration is inversely related to the intake and plasma levels of folate and vitamin B-6 as well as vitamin B-12 plasma levels. Almost two-thirds of the prevalence of high homocysteine is attributable to low vitamin status or intake. Elevated homocysteine concentrations in plasma are a risk factor for prevalence of extracranial carotid artery stenosis of at least 25% in both men and women. Prospectively elevated plasma homocysteine is associated with increased total and CVD mortality, increased incidence of stroke, increased incidence of dementia and Alzheimer's disease, increased incidence of bone fracture, and higher prevalence of chronic heart failure. This multitude of relationships between elevated plasma total homocysteine and diseases that afflict the elderly point to the existence of a common denominator that may be responsible for these diseases. Whether this denominator is homocysteine itself or whether homocysteine is merely a marker remains to be determined.
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Affiliation(s)
- Jacob Selhub
- Vitamin Metabolism and Aging Laboratory, Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.
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Tan H, Jiang X, Yang F, Li Z, Liao D, Trial J, Magera MJ, Durante W, Yang X, Wang H. Hyperhomocysteinemia inhibits post-injury reendothelialization in mice. Cardiovasc Res 2006; 69:253-62. [PMID: 16226235 PMCID: PMC4400842 DOI: 10.1016/j.cardiores.2005.08.016] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2005] [Revised: 08/26/2005] [Accepted: 08/29/2005] [Indexed: 01/01/2023] Open
Abstract
OBJECTIVE Hyperhomocysteinemia (HHcy) is a risk factor for cardiovascular disease and has been reported to inhibit endothelial cell (EC) growth. Notwithstanding, precisely how HHcy regulates EC growth in vivo remains unknown. In this study, we established a mouse model of endothelial injury and reendothelialization and examined the role and mechanism of HHcy in endothelial repair. METHODS AND RESULTS A mouse model of carotid artery air-dry endothelium denudation and reendothelialization was established and used to evaluate post-injury endothelial repair in mice with the gene deletion of cystathionine-beta-synthase (CBS). Moderate and severe HHcy were induced in CBS+/+ and CBS-/+ mice through a high-methionine diet. Post-injury reendothelialization, which correlated with increased post-injury neointima formation, was impaired in severe HHcy mice. To elucidate the underlying mechanism, we examined circulating endothelial progenitor cells (EPC) in HHcy mice and studied the effect of homocysteine (Hcy) on proliferation, migration, and adhesion of human umbilical vein endothelial cells (HUVEC). The peripheral EPC population was not significantly altered in HHcy mice. Hcy had a profound inhibitory effect on EC proliferation and migration at physiologically relevant concentrations and inhibited EC adhesion at concentrations of 200 microM and higher. CONCLUSION We have established a convenient and accurate mouse model of carotid injury in which the reendothelialization process can be precisely quantified. In addition, we have observed impaired reendothelialization and increased neointimal formation in severe HHcy mice. The capacity of Hcy to inhibit proliferation and migration of EC may be responsible for impaired reendothelialization and contribute to arteriosclerosis in HHcy.
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Affiliation(s)
- Hongmei Tan
- Department of Medicine, Baylor College of Medicine, United States
- VA Medical Center, Houston, Texas 77030, United States
- Sun Yat-sen University School of Medicine, Guangzhou, China
| | - Xiaohua Jiang
- Department of Medicine, Baylor College of Medicine, United States
- VA Medical Center, Houston, Texas 77030, United States
| | - Fan Yang
- Department of Medicine, Baylor College of Medicine, United States
- VA Medical Center, Houston, Texas 77030, United States
| | - Zhaohui Li
- Department of Medicine, Baylor College of Medicine, United States
- VA Medical Center, Houston, Texas 77030, United States
| | - Dan Liao
- Department of Medicine, Baylor College of Medicine, United States
- VA Medical Center, Houston, Texas 77030, United States
| | - JoAnn Trial
- Department of Medicine, Baylor College of Medicine, United States
| | | | - William Durante
- Department of Medicine, Baylor College of Medicine, United States
- Department of Pharmacology, Baylor College of Medicine, United States
- VA Medical Center, Houston, Texas 77030, United States
| | - Xiaofeng Yang
- Department of Medicine, Baylor College of Medicine, United States
| | - Hong Wang
- Department of Medicine, Baylor College of Medicine, United States
- VA Medical Center, Houston, Texas 77030, United States
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