Effects of Hormone-Replacement Therapy on Fibrinolysis in Postmenopausal Women

Koh, Kwang Kon; Mincemoyer, Rita; Bui, Minh; Csákó, György; Pucino, Frank; Guetta, Victor; Waclawiw, Myron A.; Cannon, Richard O.

doi:10.1097/00006254-199707000-00019

Cited by 73 publications

(131 citation statements)

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“…31 Hormone replacement therapy also effectively lowers PAI-1 levels in postmenopausal women. 35 Both of these therapeutic strategies, however, have multiple other effects that contribute to, and even possibly complicate, their effects in terms of vasculoprotection. The present study describes a novel mechanism for protecting the vasculature from the pathological consequences of long-term inhibition of NOS.…”

Section: Discussionmentioning

confidence: 99%

Plasminogen Activator Inhibitor-1 Deficiency Prevents Hypertension and Vascular Fibrosis in Response to Long-term Nitric Oxide Synthase Inhibition

et al. 2001

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Background-Long-term inhibition of nitric oxide synthase (NOS) is known to induce hypertension and perivascular fibrosis. Recent evidence also suggests that long-term NOS inhibition induces expression of plasminogen activator inhibitor-1 (PAI-1) in vascular tissues and that PAI-1 may contribute to the development of fibrosis after chemical or ionizing injury. On the basis of these observations, we hypothesized that PAI-1 may influence the vascular response to long-term NOS inhibition by N -nitro-L-arginine methyl ester (L-NAME). Methods and Results-We compared the temporal changes in systolic blood pressure and coronary perivascular fibrosis in PAI-1-deficient (PAI-1 Ϫ/Ϫ ) and wild-type (WT) male mice (Nϭ6 per group). At baseline, there were no significant differences in blood pressure between groups. After initiation of L-NAME, systolic blood pressure increased in both groups at 2 weeks. Over an 8-week study period, systolic blood pressure increased to 141Ϯ3 mm Hg in WT animals versus 112Ϯ4 mm Hg in PAI-1 Ϫ/Ϫ mice (PϽ0.0001). The extent of coronary perivascular fibrosis increased significantly in L-NAME-treated WT mice (PϽ0.01 versus PAI-1 Ϫ/Ϫ mice). Cardiac type I collagen mRNA expression was greater in control (PϽ0.01) and L-NAME-treated PAI-1 Ϫ/Ϫ (PϽ0.05) groups than in control WT mice, indicating that PAI-1 deficiency prevents the increase of collagen deposition by promoting matrix degradation. Conclusions-These findings suggest that PAI-1 deficiency alone is sufficient to protect against the structural vascular changes that accompany hypertension in the setting of long-term NOS inhibition. Direct inhibition of vascular PAI-1 activity may provide a new therapeutic strategy for the prevention of arteriosclerotic cardiovascular disease.

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Section: Discussionmentioning

confidence: 99%

Plasminogen Activator Inhibitor-1 Deficiency Prevents Hypertension and Vascular Fibrosis in Response to Long-term Nitric Oxide Synthase Inhibition

et al. 2001

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“…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%

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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“…However, these changes in lipid profile only contribute to approximately 25% of the protective effect of estrogens 4 . Other potential mechanisms of action of estrogens may include protection against LDL oxidation 5 , reduction in lipoprotein(a), potentiation of fibrinolysis 6 , and increase in insulin sensitivity. In the arteries, estrogens improve vasodilating function, decrease calcification, secretion of cell adhesion molecules (E-selectin, ICAM-1, and VCAM-1), and formation of atherosclerotic lesions 7 .…”

Section: Lipid Peroxidation and Nitric Oxide Inactivation In Postmenomentioning

confidence: 99%

Lipid peroxidation and nitric oxide inactivation in postmenopausal women

Pereira

Bertolami

Faludi

et al. 2003

Arq. Bras. Cardiol.

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Original ArticleCardiovascular diseases are less prevalent in premenopausal women and in those receiving hormone replacement therapy as compared with postmenopausal women and men 1 . This protective effect is attributed to estrogens, and one of the mechanisms of action may be related to the metabolism of plasma lipoproteins 2 .Estrogens reduce LDL-cholesterol and increase HDLcholesterol 3 . However, these changes in lipid profile only contribute to approximately 25% of the protective effect of estrogens 4 . Other potential mechanisms of action of estrogens may include protection against LDL oxidation 5 , reduction in lipoprotein(a), potentiation of fibrinolysis 6 , and increase in insulin sensitivity. In the arteries, estrogens improve vasodilating function, decrease calcification, secretion of cell adhesion molecules (E-selectin, ICAM-1, and VCAM-1), and formation of atherosclerotic lesions 7 .Direct action of estrogens on the arterial wall has also been demonstrated. The administration of estrogens for prolonged periods inhibits the deposition of cholesterol in the arteries and thickening of the intima in monkeys and rabbits fed an atherogenic diet 8 . However, the mechanisms determining the direct effects of estrogens on the arterial wall have not been completely elucidated. The hemodynamic effects may be partially measured by the activity of estrogens on the synthesis of endothelial nitric oxide 9 . Estrogens have been suggested to possibly improve endothelial function and decrease the risks of atherosclerosis in premenopausal women. Nitric oxide has its bioactivity reduced in postmenopausal women. However, it is not clear whether this occurs due to its lower production by nitric oxide synthase, or whether nitric oxide is inactivated by reaction with the superoxide radical also generated by endothelial cells, forming the peroxynitrite anion (ONOO -), which is a strong oxidizing agent.Peroxynitrite is decomposed into other reactive oxygen species ( fig. 1) 10 and reacts with tyrosine residues of proteins to form nitrotyrosine 11 . Although little is known NOx, nitrotyrosine, COx, CE 18:2 -OOH, and PC-OOH were higher in the postmenopausal period (33.8±22.3 µM; 230±130 nM; 55±19 ng/µL; 17±8.7 nM; 2775±460 nM, respectively) Objective -To assess the effect of endogenous estrogens on the bioavailability of nitric oxide (·NO) and in the formation of lipid peroxidation products in pre-and postmenopausal women. Methods -NOx and S-nitrosothiols were determined by gaseous phase chemiluminescence, nitrotyrosine was determined by ELISA, COx (cholesterol oxides) by gas chromatography, and cholesteryl linoleate hydroperoxides (CE 18:2 -OOH), trilinolein (TG 18:2 -OOH), and phospholipids (PC-OOH) by HPLC in samples of plasma. Results -The concentrations of

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Effects of Hormone-Replacement Therapy on Fibrinolysis in Postmenopausal Women

Cited by 73 publications

References 0 publications

Plasminogen Activator Inhibitor-1 Deficiency Prevents Hypertension and Vascular Fibrosis in Response to Long-term Nitric Oxide Synthase Inhibition

Plasminogen Activator Inhibitor-1 Deficiency Prevents Hypertension and Vascular Fibrosis in Response to Long-term Nitric Oxide Synthase Inhibition

Simvastatin Combined With Ramipril Treatment in Hypercholesterolemic Patients

Lipid peroxidation and nitric oxide inactivation in postmenopausal women

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