Inhibition of the protective effect of estrogen by progesterone in experimental atherosclerosis

Hanke, Hartmut; Hanke, Sybille; Bruck, Birgit; Brehme, Ute; Gugel, Natalia; Finking, Gerald; Mück, A. O.; Schmahl, F. W.; Hombach, Vinzenz; Haasis, R

doi:10.1016/0021-9150(95)05710-2

Cited by 77 publications

(42 citation statements)

References 28 publications

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“…However, the contribution of progesterone to the replacement regime has been controversial. Although experimental studies evaluating intimal thickness (37) and bromodeoxyuridine incorporation (38) conclude that progesterone directly inhibits the atheroprotective effect of estrogen, several epidemiological and in vivo studies demonstrate otherwise (39,40). The finding that progesterone inhibits re-endothelialization of denuded aortae suggests that this hormone could have an opposite effect on estradiol in endothelial repair of denuded atherosclerotic lesions (41).…”

Section: Discussionmentioning

confidence: 93%

Progesterone Regulates Proliferation of Endothelial Cells

Vázquez

Rodrı́guez-Manzaneque

Lydon

et al. 1999

Journal of Biological Chemistry

124

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The use of steroid hormones in postmenopausal replacement therapy has been associated with prevention of cardiovascular disease. Although the contribution of estradiol to endothelial cell function has been addressed, little information is available on the effect of progestins on this cell type. Here, we provide direct evidence for the presence of functional nuclear progesterone receptor in endothelial cells and demonstrate that physiological levels of progesterone inhibit proliferation through a nuclear receptor-mediated mechanism. The effects of progesterone were blocked by pretreatment with a progesterone receptor antagonist, and progesterone receptor-deficient endothelial cells failed to respond to the hormone. We evaluated the effect of progesterone by analysis of aorta re-endothelialization experiments in wild-type and progesterone receptor knockout mice. The rate of re-endothelialization was significantly decreased in wild-type mice when in the presence of progesterone, whereas there was no difference between control and progesterone-treated progesterone receptor knockout mice. FACS analysis showed that progestins arrest endothelial cell cycle in G 1 . The lag in cell cycle progression involved reduction in cyclindependent kinase activity, as shown by down-regulation in retinoblastoma protein phosphorylation. In addition, treatment of endothelial cells with progestins altered the expression of cyclin E and A in accordance with G 1 arrest. These results have important implications to our current knowledge of the effect of steroids on endothelial cell function and to the overall contribution of progesterone to vascular repair.

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Section: Discussionmentioning

confidence: 93%

Progesterone Regulates Proliferation of Endothelial Cells

Vázquez

Rodrı́guez-Manzaneque

Lydon

et al. 1999

Journal of Biological Chemistry

124

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“…3,4,6,29 -32 Progestagens can have adverse effects on lipoprotein concentrations 33,34 and negatively affect the beneficial effects of estradiol on atherosclerotic lesion formation. [35][36][37][38] Other investigations, however, showed no negative effect of progestagens on the beneficial effects of estrogen on the vessel wall. 13,14,19 Tibolone (Org OD14), a synthetic steroid [(7␣,17␣)-17-hydroxy-7-methyl-19-norpregn-5(10)-en-20-yn-3-one] with a combination of estrogenic, androgenic, and progestogenic properties, is clinically effective for the treatment of climacteric symptoms 39,40 and the treatment and prevention of osteoporosis in postmenopausal women, 41 with no stimulatory effect on the endometrium.…”

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confidence: 99%

Tibolone Prevents Atherosclerotic Lesion Formation in Cholesterol-Fed, Ovariectomized Rabbits

Zandberg¹,

Peters²,

Demacker³

et al. 1998

ATVB

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Abstract-Tibolone (Org OD14), a synthetic steroid with estrogenic and progestogenic/androgenic properties, is clinically effective for the treatment of climacteric symptoms and the prevention and treatment of osteoporosis in postmenopausal women. The effect on atherogenesis, however, is not known. In the current study, we investigated the effect of tibolone in comparison with that of estradiol and norethisterone acetate on atherogenesis in 140 ovariectomized New Zealand White rabbits that had been induced by an atherogenic diet (0.4% cholesterol, 20 weeks). Tibolone at 18, 6, or 2 mg/d orally completely prevented cholesterol accumulation and fatty streak formation in the aorta; the impairment of endothelium-dependent smooth muscle relaxation of the aorta; and complex lesion formation after endothelial denudation in the carotid artery. Tibolone also reduced the increased postovariectomy plasma lipid concentrations. Analysis of the results, however, indicated that a substantial part of the strong, beneficial effects were plasma lipid independent. Compared with subcutaneous estradiol decanoate (150 g once weekly) and oral 17␤-estradiol (4 mg/d), the effects of tibolone were more pronounced at equipotent uterotropic activity. Norethisterone acetate (1 mg/d) did not affect atherosclerotic lesion formation. There are no indications that the progestogenic/androgenic properties of tibolone counteracted its atheroprotective effect on the vessel wall. Therefore, tibolone has the intrinsic potential to be a compound that protects the arterial vessel wall against atherosclerotic processes.

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“…It is important to note that progestins differ in their anti-or proatherosclerotic properties. For instance, medroxyprogesterone, a synthetic progestin, has been associated with adverse cardiovascular effects, whereas the naturally occurring P, which we used in our study, had favorable properties in the vasculature (8).…”

Section: Discussionmentioning

confidence: 94%

Response to sex hormones differs in atherosclerosis-susceptible and -resistant mice

Potier

Karl

Elliot

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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; 10.1152/ajpendo. 00451.2002.-Genetic factors that determine the degree of susceptibility to atherosclerosis may also influence the effects of estrogens and progestins in arterial vessel disease. We examined and compared estrogen receptor (ER) and progesterone receptor (PR) expression and the effects of 17␤-estradiol (E 2) and progesterone (P) on collagen synthesis and matrix metalloproteinase (MMP) activities in the aortic arch and in cultured aortic smooth muscle cells (ASMC) of atherosclerosis-susceptible (C57Bl6/J, B6) or -resistant (C3H/HeJ, C3H) mice. ER␣, ER␤, and PR levels were higher in the aorta and ASMC of atherosclerosis-susceptible B6 mice. In transfection studies using an estrogen response element-driven reporter plasmid, E 2 elicited a Ͼ2-fold increase in luciferase activity in ASMC of B6 (B6-ASMC), which demonstrated the transcriptional activity of ER in atherosclerosis-susceptible cells. Importantly, the response of endogenous target genes to E 2 and P was different in B6-ASMC and C3H-ASMC. E2 decreased collagen synthesis but had no effect on MMP activities in B6-ASMC. P decreased MMP-2 and MMP-9 activity in B6-ASMC. In contrast, E 2 increased MMP-2 and decreased MMP-9 activity but had no effect on collagen synthesis in C3H-ASMC. P had no effect on collagen synthesis and MMP activity in C3H-ASMC. These differences in response to sex hormones may have important implications for women who receive hormone replacement therapy. vascular smooth muscle cells; estrogen receptor; progesterone receptor; matrix metalloproteinase; collagen ATHEROSCLEROSIS AND CORONARY HEART DISEASE (CHD) remain the major causes of morbidity and mortality in the United States (24). The development and progression of atherosclerosis are determined by genetic as well as environmental factors. The development of atherosclerosis is under the control of multiple genes in humans as well as in rodents. Paigen and colleagues (15,(21)(22)(23) found that inbred mouse strains differ significantly in their susceptibility to diet-induced atherosclerosis and thereby defined "atherosclerosis-susceptible or atherosclerosis-resistant genetic backgrounds." C57Bl6/J (B6) mice fed a high-fat diet develop conspicuous atherosclerotic lesions, whereas C3H/HeJ (C3H) mice are resistant to diet-induced atherosclerosis. Comparative analysis of these mouse models provides a unique opportunity to study the impact of the genetic background on the expression of female sex hormone receptors and their effects on molecules involved in the protection or progression of atherosclerosis such as collagens and matrix metalloproteinase (MMP). An imbalance of collagen synthesis and degradation by MMP in the vascular wall have an important role in the pathogenesis of atherosclerosis (4). An altered response to estrogens and/or progestins may contribute to this imbalance, since these sex steroids are known to regulate collagen synthesis and MMP activity in reproductive organs (19,29) and in large and small vascular beds (30), including the renal glomerulus (7,17,26)....

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Inhibition of the protective effect of estrogen by progesterone in experimental atherosclerosis

Cited by 77 publications

References 28 publications

Progesterone Regulates Proliferation of Endothelial Cells

Progesterone Regulates Proliferation of Endothelial Cells

Tibolone Prevents Atherosclerotic Lesion Formation in Cholesterol-Fed, Ovariectomized Rabbits

Response to sex hormones differs in atherosclerosis-susceptible and -resistant mice

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