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Lieben Louis X, Meikle Z, Chan L, DeGagne G, Cummer R, Meikle S, Krishnan S, Yu L, Netticadan T, Wigle JT. Divergent Effects of Resveratrol on Rat Cardiac Fibroblasts and Cardiomyocytes. Molecules 2019; 24:molecules24142604. [PMID: 31319579 PMCID: PMC6680709 DOI: 10.3390/molecules24142604] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 07/11/2019] [Accepted: 07/12/2019] [Indexed: 11/27/2022] Open
Abstract
In this study, we tested the potential cardioprotective effects of the phytoalexin resveratrol (Rsv) on primary adult rat cardiac fibroblasts (CF), myofibroblasts (MF) and cardiomyocytes. Adult rat CF and cardiomyocytes were isolated from male 10-week old Sprague–Dawley rats, cultured for either 24 h (cardiomyocytes) or 48 h (CF) before treatments. To isolate MF, CF were trypsinized after 48 h in culture, seeded in fresh plates and cultured for 24 h prior to treatment. All three cells were then treated for a further 24 h with a range of Rsv doses. In CF and MF, cell proliferation, viability, apoptosis assays were performed with or without Rsv treatment for 24 h. In cardiomyocytes, cell viability and apoptosis assay were performed 24 h after treatment. In separate experiments, CF was pre-incubated with estrogen, tamoxifen and fulvestrant for 30 min prior to Rsv treatment. Rsv treatment decreased proliferation of both fibroblasts and myofibroblasts. Rsv treatment also increased the proportion of dead CF and MF in a dose dependent manner. However, treatment with Rsv did not induce cell death in adult cardiomyocytes. There was an increase in the percentage of cells with condensed nuclei with Rsv treatment in both CF and MF, but not in cardiomyocytes. Treatment with estrogen, tamoxifen and fulvestrant alone or in combination with Rsv did not have any additional effects on CF survival. Our results demonstrate that treatment with Rsv can inhibit cell proliferation and induce cell death in rat CF and MF, while not affecting cardiomyocyte survival. We also demonstrated that the induction of cell death in CF with Rsv treatment was independent of estrogen receptor alpha (ERα) signaling.
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Affiliation(s)
- Xavier Lieben Louis
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
| | - Zach Meikle
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
| | - Laura Chan
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
| | - Garret DeGagne
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada
| | - Rebecca Cummer
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
| | - Shannon Meikle
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
| | - Sampath Krishnan
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
- Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
| | - Liping Yu
- Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada
- Agriculture and Agri-Food Canada, Winnipeg Winnipeg, MB R2H 2A6, Canada
| | - Thomas Netticadan
- Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada.
- Agriculture and Agri-Food Canada, Winnipeg Winnipeg, MB R2H 2A6, Canada.
- Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
| | - Jeffrey T Wigle
- Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada.
- Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.
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Louis XL, Raj P, Chan L, Zieroth S, Netticadan T, Wigle JT. Are the cardioprotective effects of the phytoestrogen resveratrol sex-dependent? 1. Can J Physiol Pharmacol 2018; 97:503-514. [PMID: 30576226 DOI: 10.1139/cjpp-2018-0544] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Cardiovascular disease (CVD) is the number one cause of death in both men and women. Younger women have a lower risk for CVD, but their risk increases considerably after menopause when estrogen levels decrease. The cardiovascular protective properties of estrogen are mediated through decreasing vascular inflammation and progression of atherosclerosis, decreasing endothelial cell damage by preventing apoptosis and anti-hypertrophic mechanisms. Estrogen also regulates glucose and lipid levels, which are 2 important risk factors for CVD. Resveratrol (RES), a cardioprotective polyphenolic compound, is classified as a phytoestrogen due its capacity to bind to and modulate estrogen receptor signalling. Due to its estrogen-like property, we speculate that the cardioprotective effects of RES treatment could be sex-dependent. Based on earlier reports and more recent data from our lab presented here, we found that RES treatment may have more favourable cardiovascular outcomes in females than in males. This review will discuss estrogen- and phytoestrogen-mediated cardioprotection, with a specific focus on sex-dependent effects reported in preclinical and clinical studies.
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Affiliation(s)
- Xavier Lieben Louis
- a Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada.,b Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R2E 3N4, Canada
| | - Pema Raj
- c Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R2E 0J9, Canada.,d Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Albrechtsen, Research Centre, Winnipeg, MB R2H 2A6, Canada
| | - Laura Chan
- a Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada.,b Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R2E 3N4, Canada
| | - Shelley Zieroth
- c Department of Physiology and Pathophysiology, University of Manitoba, Winnipeg, MB R2E 0J9, Canada.,e Section of Cardiology, Department of Medicine, University of Manitoba, Winnipeg, MB R3A 1R9, Canada
| | - Thomas Netticadan
- d Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Albrechtsen, Research Centre, Winnipeg, MB R2H 2A6, Canada.,f Agriculture and Agri-Food Canada, Winnipeg, MB R3C 3G7, Canada
| | - Jeffrey T Wigle
- a Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Winnipeg, MB R2H 2A6, Canada.,b Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB R2E 3N4, Canada
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Tsai CC, Tey SL, Lee MC, Liu CW, Su YT, Huang SC. Mechanism of resveratrol-induced relaxation of the guinea pig fundus. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2018; 43:55-59. [PMID: 29747754 DOI: 10.1016/j.phymed.2018.03.061] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/16/2017] [Revised: 02/10/2018] [Accepted: 03/21/2018] [Indexed: 06/08/2023]
Abstract
BACKGROUND Resveratrol is a polyphenolic compound that can be isolated from plants and also is a constituent of red wine. Resveratrol induces relaxation of vascular smooth muscle and may prevent cardiovascular diseases. PURPOSE Impaired gastric accommodation plays an important role in functional dyspepsia and fundic relaxation and is a therapeutic target of functional dyspepsia. Although drugs for fundic relaxation have been developed, these types of drugs are still rare. The purpose of this study was to investigate the relaxant effects of resveratrol in the guinea pig fundus. STUDY DESIGN We studied the relaxant effects of resveratrol in the guinea pig fundus. In addition, we investigated the mechanism of resveratrol-induced relaxation on the guinea pig fundus by using tetraethylammonium (a non-selective potassium channel blocker), apamine (a selective inhibitor of the small conductance calcium-activated potassium channel), iberiotoxin (an inhibitor of large conductance calcium-activated potassium channels), glibenclamide (an ATP-sensitive potassium channel blocker), KT 5720 (a cAMP-dependent protein kinase A inhibitor), KT 5823 (a cGMP-dependent protein kinase G inhibitor), NG-nitro-L-arginine (a competitive inhibitor of nitric oxide synthase), tetrodotoxin (a selective neuronal Na+ channel blocker), ω-conotoxin GVIA (a selective neuronal Ca2+ channel blocker) and G-15 (a G-protein coupled estrogen receptor antagonist). RESULTS The results of this study showed that resveratrol has potent and dose-dependent relaxant effects on the guinea pig fundic muscle. In addition, the results showed that resveratrol-induced relaxation of the guinea pig fundus occurs through nitric oxide and ATP-sensitive potassium channels. CONCLUSION This study provides the first evidence concerning the relaxant effects of resveratrol in the guinea pig fundic muscle strips. Furthermore, resveratrol may be a potential drug to relieve gastrointestinal dyspepsia.
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Affiliation(s)
- Ching-Chung Tsai
- Department of Pediatrics, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan No.1, Yi-Da Road, Yan-Chao, Kaohsiung City, Taiwan, R.O.C.; School of Chinese Medicine for Post Baccalaureate, I-Shou University, Kaohsiung, Taiwan No. 8, Yi-Da Road, Yan-Chao, Kaohsiung City, Taiwan, R.O.C..
| | - Shu-Leei Tey
- Department of Pediatrics, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan No.1, Yi-Da Road, Yan-Chao, Kaohsiung City, Taiwan, R.O.C..
| | - Ming-Che Lee
- Department of General Surgery, Tzu Chi General Hospital and Tzu Chi University, No.707, Section 3, Chung-Yang Road, Hualien, Taiwan, R.O.C..
| | - Ching-Wen Liu
- School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan No.100, Shih-Chuan 1st Road, Sanmin District, Kaohsiung City, Taiwan, R.O.C..
| | - Yu-Tsun Su
- Department of Pediatrics, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan No.1, Yi-Da Road, Yan-Chao, Kaohsiung City, Taiwan, R.O.C..
| | - Shih-Che Huang
- Department of Internal Medicine, Shosanbetsu Village Clinic, 122-8 Shosanbetsu, Shosanbetsu Village, Tomamae-Gun, Hokkaido 078-4421, Japan.
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P-gp, MRP2 and OAT1/OAT3 mediate the drug-drug interaction between resveratrol and methotrexate. Toxicol Appl Pharmacol 2016; 306:27-35. [PMID: 27377006 DOI: 10.1016/j.taap.2016.06.030] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2016] [Revised: 06/26/2016] [Accepted: 06/29/2016] [Indexed: 01/27/2023]
Abstract
The purpose of present study was to investigate the effect of resveratrol (Res) on altering methotrexate (MTX) pharmacokinetics and clarify the related molecular mechanism. Res significantly increased rat intestinal absorption of MTX in vivo and in vitro. Simultaneously, Res inhibited MTX efflux transport in MDR1-MDCK and MRP2-MDCK cell monolayers, suggesting that the target of drug interaction was MDR1 and MRP2 in the intestine during the absorption process. Furthermore, there was a significant decrease in renal clearance of MTX after simultaneous intravenous administration. Similarly, MTX uptake was markedly inhibited by Res in rat kidney slices and hOAT1/3-HEK293 cell, indicating that OAT1 and OAT3 were involved in the drug interaction in the kidney. Additionally, concomitant administration of Res decreased cytotoxic effects of MTX in hOAT1/3-HEK293 cells, and ameliorated nephrotoxicity caused by MTX in rats. Conversely, intestinal damage caused by MTX was not exacerbated after Res treatment. In conclusion, Res enhanced MTX absorption in intestine and decreased MTX renal elimination by inhibiting P-gp, MRP2, OAT1 and OAT3 in vivo and in vitro. Res improved MTX-induced renal damage without increasing intestinal toxicity.
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Polyphenols and Polypeptides in Chinese Rice Wine Inhibit Homocysteine-induced Proliferation and Migration of Vascular Smooth Muscle Cells. J Cardiovasc Pharmacol 2016; 67:482-90. [DOI: 10.1097/fjc.0000000000000370] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Enhancement effect of resveratrol on the intestinal absorption of bestatin by regulating PEPT1, MDR1 and MRP2 in vivo and in vitro. Int J Pharm 2015; 495:588-598. [DOI: 10.1016/j.ijpharm.2015.09.042] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2015] [Revised: 08/31/2015] [Accepted: 09/18/2015] [Indexed: 02/04/2023]
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Shin JA, Oh S, Ahn JH, Park EM. Estrogen receptor-mediated resveratrol actions on blood-brain barrier of ovariectomized mice. Neurobiol Aging 2014; 36:993-1006. [PMID: 25448605 DOI: 10.1016/j.neurobiolaging.2014.09.024] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Revised: 09/05/2014] [Accepted: 09/25/2014] [Indexed: 12/13/2022]
Abstract
To test whether resveratrol provides benefits via estrogen receptors (ERs) in the blood-brain barrier of estrogen-deficient females, ovariectomized mice were treated with resveratrol then were subjected to transient middle cerebral artery occlusion (MCAO). Compared with vehicle treatment, resveratrol reduced infarct volume and neurologic deficits after MCAO. Basal tight junction (TJ) protein levels in the brain were increased by resveratrol. After MCAO, blood-brain barrier breakdown reduced levels of TJ proteins, and induction of HIF-1α and VEGF were attenuated by resveratrol. These effects were reversed by the ERs antagonist, ICI182,780. In mouse brain, endothelial cells (bEnd.3) exposed to hypoxia, resveratrol treatment protected the cells against cytotoxicity, increases of paracellular permeability and changes in levels of TJ protein and HIF-1α/VEGF proteins. These effects were reversed by ICI182,780 but not by specific ERα or ERβ antagonists, indicating nonspecific ER mediated effects. Altogether, these results showed that neuroprotective effects of resveratrol in ovariectomized mice were mediated by ERs and associated with tightening of blood-brain barrier, suggesting that resveratrol can be an alternative to estrogens to protect the brains of estrogen-deficient females against ischemic insult.
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Affiliation(s)
- Jin A Shin
- Department of Pharmacology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Seikwan Oh
- Department of Neuroscience, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Jung-Hyuck Ahn
- Department of Biochemistry, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Eun-Mi Park
- Department of Pharmacology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
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Artero A, Artero A, Tarín JJ, Cano A. The impact of moderate wine consumption on health. Maturitas 2014; 80:3-13. [PMID: 25449821 DOI: 10.1016/j.maturitas.2014.09.007] [Citation(s) in RCA: 105] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Accepted: 09/20/2014] [Indexed: 12/29/2022]
Abstract
Wine is a traditional beverage that has been associated with both healthy and harmful effects. Conceptions like the so-called "French paradox" or the beneficial impact of the Mediterranean diet suggest benefit. Wine has a complex composition, which is affected by whether it is red or white or by other variables, like the variety of grapes or others. Alcohol and phenolic compounds have been attributed a participation in the benefits ascribed to wine. The case of alcohol has been extensively studied, but the key question is whether wine offers additional benefits. Resveratrol, a non-flavonoid compound, and quercetin, a flavonol, have received particular attention. There is much experimental work confirming a beneficial balance for both substances, particularly resveratrol, in various organs and systems. The pharmacological dosages used in many of those experiments have shed doubt, however, on the clinical translation of those findings. Clinical studies are limited by their observational nature as well as for the difficulties to abstract the benefits of wine from other confounders. Notwithstanding the doubts, there is reasonable unanimity in beneficial effects of moderate wine consumption in cardiovascular disease, diabetes, osteoporosis, maybe neurological diseases, and longevity. Observations are less enthusiastic in what refers to cancer. While considering these limitations, clinicians may spread the message that the balance of moderate wine consumption seems beneficial.
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Affiliation(s)
- Ana Artero
- Department of Endocrinology and Nutrition, Hospital Clínico Universitario, Av Blasco Ibáñez 17, 46010 Valencia, Spain.
| | - Arturo Artero
- Department of Internal Medicine, Hospital Univesitario Dr. Peset, Av Gaspar Aguilar 90, 46017 Valencia, Spain; Department of Medicine, University of Valencia, Valencia, Av Blasco Ibáñez 15, 46010 Valencia, Spain.
| | - Juan J Tarín
- Department of Functional Biology and Physical Anthropology, School of Biological Sciences, Burjasot Campus, University of Valencia, Valencia, Spain.
| | - Antonio Cano
- Service of Obstetrics and Gynecology, Clínico University Hospital, Av Blasco Ibáñez 17, 46010 Valencia, Spain; Department of Pediatrics, Obstetrics and Gynecology, University of Valencia, Av Blasco Ibáñez 15, 46010 Valencia, Spain.
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Khurana S, Venkataraman K, Hollingsworth A, Piche M, Tai TC. Polyphenols: benefits to the cardiovascular system in health and in aging. Nutrients 2013; 5:3779-827. [PMID: 24077237 PMCID: PMC3820045 DOI: 10.3390/nu5103779] [Citation(s) in RCA: 269] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2013] [Revised: 07/25/2013] [Accepted: 08/04/2013] [Indexed: 12/26/2022] Open
Abstract
Numerous studies have demonstrated the importance of naturally occurring dietary polyphenols in promoting cardiovascular health and emphasized the significant role these compounds play in limiting the effects of cellular aging. Polyphenols such as resveratrol, epigallocatechin gallate (EGCG), and curcumin have been acknowledged for having beneficial effects on cardiovascular health, while some have also been shown to be protective in aging. This review highlights the literature surrounding this topic on the prominently studied and documented polyphenols as pertaining to cardiovascular health and aging.
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Affiliation(s)
- Sandhya Khurana
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +705-662-7239; Fax: +705-675-4858
| | - Krishnan Venkataraman
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +705-662-7239; Fax: +705-675-4858
| | - Amanda Hollingsworth
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +705-662-7239; Fax: +705-675-4858
| | - Matthew Piche
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +705-662-7239; Fax: +705-675-4858
| | - T. C. Tai
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +705-662-7239; Fax: +705-675-4858
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Abstract
Although the increased lifespan of our populations illustrates the success of modern medicine, the risk of developing many diseases increases exponentially with old age. Caloric restriction is known to retard ageing and delay functional decline as well as the onset of disease in most organisms. Studies have implicated the sirtuins (SIRT1-SIRT7) as mediators of key effects of caloric restriction during ageing. Two unrelated molecules that have been shown to increase SIRT1 activity in some settings, resveratrol and SRT1720, are excellent protectors against metabolic stress in mammals, making SIRT1 a potentially appealing target for therapeutic interventions. This Review covers the current status and controversies surrounding the potential of sirtuins as novel pharmacological targets, with a focus on SIRT1.
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Masood DEN, Roach EC, Beauregard KG, Khalil RA. Impact of sex hormone metabolism on the vascular effects of menopausal hormone therapy in cardiovascular disease. Curr Drug Metab 2011; 11:693-714. [PMID: 21189141 DOI: 10.2174/138920010794233477] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2010] [Accepted: 10/25/2010] [Indexed: 12/24/2022]
Abstract
Epidemiological studies have shown that cardiovascular disease (CVD) is less common in pre-menopausal women (Pre-MW) compared to men of the same age or post-menopausal women (Post-MW), suggesting cardiovascular benefits of estrogen. Estrogen receptors (ERs) have been identified in the vasculature, and experimental studies have demonstrated vasodilator effects of estrogen/ER on the endothelium, vascular smooth muscle (VSM) and extracellular matrix. Several natural and synthetic estrogenic preparations have been developed for relief of menopausal vasomotor symptoms. However, whether menopausal hormone therapy (MHT) is beneficial in postmenopausal CVD remains controversial. Despite reports of vascular benefits of MHT from observational and experimental studies, randomized clinical trials (RCTs), such as the Heart and Estrogen/progestin Replacement Study (HERS) and the Women's Health Initiative (WHI), have suggested that, contrary to expectations, MHT may increase the risk of CVD. These discrepancies could be due to agerelated changes in sex hormone synthesis and metabolism, which would influence the effective dose of MHT and the sex hormone environment in Post-MW. Age-related changes in the vascular ER subtype, structure, expression, distribution, and post-ER signaling pathways in the endothelium and VSM, along with factors related to the design of RCTs, preexisting CVD condition, and structural changes in the blood vessels architecture have also been suggested as possible causes of MHT failure in CVD. Careful examination of these factors should help in identifying the causes of the changes in the vascular effects of estrogen with age. The sex hormone metabolic pathways, the active versus inactive estrogen metabolites, and their effects on vascular function, the mitochondria, the inflammatory process and angiogenesis should be further examined. Also, the genomic and non-genomic effects of estrogenic compounds should be viewed as integrated rather than discrete responses. The complex interactions between these factors highlight the importance of careful design of MHT RCTs, and the need of a more customized approach for each individual patient in order to enhance the vascular benefits of MHT in postmenopausal CVD.
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Affiliation(s)
- Durr-e-Nayab Masood
- Vascular Surgery Research Laboratory, Division of Vascular and Endovascular Surgery, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02115, USA
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