Vascular Effects of Estrogen and Cholesterol-Lowering Therapies in Hypercholesterolemic Postmenopausal Women

Koh, Kwang Kon; Cardillo, Carmine; Bui, Minh; Hathaway, Londa; Csákó, György; Waclawiw, Myron A.; Panza, Julio A.; Cannon, Richard O.

doi:10.1161/01.cir.99.3.354

Cited by 225 publications

(142 citation statements)

References 47 publications

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“…However, in hypercholesterolemic postmenopausal women, 4 we did not observe reduction of PAI-1 by simvastatin. The reduction of PAI-1 in our present study is consistent with observation of increased PAI-1 levels in humans after infusion of angiotensin II.…”

Section: Discussioncontrasting

confidence: 86%

“…Assays for lipids, plasma nitrate (using the Griess reaction), malondialdehyde (MDA), monocyte chemoattractant protein (MCP)-1, and PAI-1 antigen were performed in duplicate by enzyme-linked immunosorbent assay (R&D Systems, Bioxytech LPO-586, OxisResearch, or Biopool for PAI-1 antigen) as previously described. 4,7,21,22 C-reactive protein (CRP) levels were determined with an immunonephelometry system according to methods described by the manufacturer (rate nephelometry; Immage, Beckman Coulter) as previously described. 23,24 …”

Section: Laboratory Assaysmentioning

confidence: 99%

“…Statins reduce LDL cholesterol and improve endothelial function, consistent with enhanced NO bioactivity. [3][4][5] ACE inhibition also improves endothelial function. 6,7 A potential mechanism of this effect is augmented NO bioactivity via diminished bradykinin degradation by ACE with activation of endothelial B 2 kinin receptors and stimulation of NO synthase activity.…”

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confidence: 99%

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Simvastatin Combined With Ramipril Treatment in Hypercholesterolemic Patients

et al. 2004

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Abstract-Mechanisms underlying biological effects of statin and angiotensin-converting enzyme inhibitor therapies differ. Thus, we studied vascular responses to combination therapy in hypercholesterolemic patients. A randomized, double-blind, placebo-controlled, crossover trial was conducted with 50 hypercholesterolemic patients with simvastatin and either placebo or ramipril (study I) and in 45 hypercholesterolemic diabetic patients with simvastatin or ramipril with placebo or simvastatin combined with ramipril (study II) for 2 months with 2 months washout. In study I simvastatin combined with ramipril significantly reduced blood pressure after 2 months. Simvastatin alone or combined with ramipril significantly changed lipoproteins, improved percent flow-mediated dilator response to hyperemia by 30Ϯ5% and 53Ϯ6%, respectively (PϽ0.001), and reduced plasma levels of malondialdehyde by 4Ϯ7% (Pϭ0.026) and 25Ϯ4% (PϽ0.001), respectively. Monocyte chemoattractant protein-1 levels decreased by 3Ϯ3% and 12Ϯ2%, respectively (Pϭ0.049 and Pϭ0.001, respectively), C-reactive protein levels changed by 0% and 18%, respectively (Pϭ0.036 and PϽ0.001, respectively), and plasminogen activator inhibitor-1 antigen levels changed by Ϫ7Ϯ7% and 17Ϯ5%, respectively (Pϭ0.828 and PϽ0.001, respectively). In study II ramipril alone did not significantly change lipoproteins and C-reactive protein levels, however, simvastatin combined with ramipril significantly changed lipoproteins and C-reactive protein levels more than ramipril alone (PϽ0.001 and Pϭ0.048 by ANOVA, respectively). Ramipril alone or simvastatin combined with ramipril significantly improved the percent flow-mediated dilator response to hyperemia (both PϽ0.001), however, simvastatin combined with ramipril showed significantly more improvement than ramipril alone (PϽ0.001 by ANOVA). Simvastatin combined with ramipril significantly improved endotheliumdependent vasodilation and fibrinolysis potential and reduced plasma levels of oxidant stress and inflammation markers in hypercholesterolemic patients. Key Words: angiotensin-converting enzyme Ⅲ atherosclerosis Ⅲ endothelial growth factors Ⅲ hypercholesterolemia Ⅲ blood pressure L arge-scale clinical studies demonstrate that statins and angiotensin-converting enzyme (ACE) inhibitor prevent or retard the progression of coronary heart disease. 1,2 The mechanisms of this apparent benefit of these therapies may include vascular effects. Statins reduce LDL cholesterol and improve endothelial function, consistent with enhanced NO bioactivity. 3-5 ACE inhibition also improves endothelial function. 6,7 A potential mechanism of this effect is augmented NO bioactivity via diminished bradykinin degradation by ACE with activation of endothelial B 2 kinin receptors and stimulation of NO synthase activity. 8 Alternatively, ACE inhibition may diminish intracellular production of superoxide anions via reduced activity of angiotensin II-dependent oxidases in the endothelium and vascular smooth muscle, 9,10 thus protecting NO from oxidant degradatio...

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Section: Discussioncontrasting

confidence: 86%

Section: Laboratory Assaysmentioning

confidence: 99%

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confidence: 99%

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Simvastatin Combined With Ramipril Treatment in Hypercholesterolemic Patients

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“…Estrogen, but not raloxifene, increases circulating CRP concentration (de Valk-de Roo et al, 1999;Walsh et al, 2000;Yildirir et al, 2002) by increasing hepatic production of CRP (Walsh et al, 2001;Skouby et al, 2002). Both estrogen and raloxifene have been reported to decrease vascular adhesion molecules (Koh et al, 1999;Blum et al, 2000) by binding to estrogen receptors on the vascular endothelium and modulating transcription of these adhesion molecules (Caulin-Glaser et al, 1996). Soy isoflavones are capable of binding to the estrogen receptor and have a similar affinity for the b-isoform (predominant form in vascular tissue) as estradiol (Gruber et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Consumption of isoflavone-rich soy protein does not alter homocysteine or markers of inflammation in postmenopausal women

et al. 2007

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Background/Objective: To investigate the effect of soy protein containing isoflavones on homocysteine (Hcy), C-reactive protein (CRP), soluble E-selectin (sE-selectin), soluble vascular adhesion molecule-1 (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1). Subject/Methods: In a randomized crossover design, 34 postmenopausal women consumed soy protein isolate (2675 g protein containing 4478 mg isoflavones per day) or milk protein isolate (2675 g protein per day) for 6 weeks each. Fasting blood samples were collected at the end of each diet period and end points analyzed by enzyme-linked immunosorbent assay. Results: Concentrations of Hcy, CRP, sE-selectin, sVCAM-1 and sICAM-1 were not different between soy and milk diet treatments. Results did not differ by equol production status or by baseline lipid concentration. Adjustment for intake of folate and methionine did not alter the Hcy results. Conclusions: These data suggest that decreasing vascular inflammation and Hcy concentration are not likely mechanisms by which soy consumption reduces coronary heart disease risk.

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“…10 -12 Increased NO production and the modulation of the lipid profile may in part underlie the well-recognized beneficial effects of estrogens on endothelial dysfunction, a prerequisite of atherosclerosis. 13,14 However, it is currently thought that endothelial dysfunction is not based on reduced production but is evoked by a decreased bioavailability of NO. 15,16 The latter is decisively influenced by the level of reactive oxygen species (ROS), such as superoxide, in the vessel wall.…”

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Endothelial Dysfunction and Oxidative Stress During Estrogen Deficiency in Spontaneously Hypertensive Rats

et al. 2001

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Background-Postmenopausal estrogen deficiency is associated with an increased cardiovascular risk, hypertension, and oxidative stress. Angiotensin type 1 (AT 1 ) receptor regulation is involved in the pathogenesis of atherosclerosis. To characterize vascular function, oxidative stress, and AT 1 receptor regulation during estrogen deficiency, ovariectomized spontaneously hypertensive rats (SHR) were investigated in comparison with sham-operated animals and with ovariectomized rats receiving estrogen replacement therapy with 17␤-estradiol. Methods and Results-Arterial blood pressure was similar in all 3 groups investigated. Five weeks after ovariectomy, endothelial dysfunction in aortic rings was observed, which was reversed by estrogen replacement therapy. Estrogen deficiency led to an enhanced vasoconstriction by angiotensin II. Vascular superoxide production was significantly increased compared with that in sham-operated rats, as measured by lucigenin chemiluminescence assays. Estrogen substitution normalized the production of free radicals in the vessel wall. Vascular AT 1 receptor expression was significantly upregulated by estrogen deficiency, as shown by quantitative reverse transcription-polymerase chain reaction, whereas endothelial NO synthase mRNA expression and NO release were unchanged. Five-week treatment of the animals with the AT 1 receptor antagonist irbesartan prevented endothelial dysfunction in ovariectomized rats and normalized the vascular production of free radicals. Conclusions-In

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Vascular Effects of Estrogen and Cholesterol-Lowering Therapies in Hypercholesterolemic Postmenopausal Women

Cited by 225 publications

References 47 publications

Simvastatin Combined With Ramipril Treatment in Hypercholesterolemic Patients

Simvastatin Combined With Ramipril Treatment in Hypercholesterolemic Patients

Consumption of isoflavone-rich soy protein does not alter homocysteine or markers of inflammation in postmenopausal women

Endothelial Dysfunction and Oxidative Stress During Estrogen Deficiency in Spontaneously Hypertensive Rats

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