Different Effects of Estrogen and Progesterone on Experimental Atherosclerosis inFemale Versus Male Rabbits

Hanke, Hartmut; Hanke, Sybille; Finking, Gerald; Muhic-Lohrer, Alexandra; ̈ck, Alfred O. Mu; Schmahl, F. W.; Haasis, R; Hombach, Vinzenz

doi:10.1161/01.cir.94.2.175

Cited by 71 publications

(43 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…33 In an immortalized cell line that does not express estrogen receptors, supraphysiological doses of 17␤-estradiol have been shown to decrease lipid uptake by macrophages 25 ; however, the effects of physiological levels of estrogen and its antagonists on foam cell formation and the mechanism of lipoprotein uptake in female and male primary human macrophages have not been studied previously. Our observation of an uptake-mediated, receptor-independent reduction in macrophage lipid loading in female cells only is consistent with other recently published work 33,34 that has also noted sex-specific effects of sex steroid hormones on atherosclerotic processes.…”

Section: Discussionmentioning

confidence: 99%

Estrogen and Progesterone Reduce Lipid Accumulation in Human Monocyte-Derived Macrophages

et al. 1999

View full text Add to dashboard Cite

Background-Males have an earlier onset and greater prevalence of clinical atherosclerosis than age-matched females, which is consistent with an atheroprotective effect of the female sex steroids, estrogen and progesterone. We therefore examined the effects of estrogen and progesterone on human foam cell formation, a key early event in atherogenesis. Methods and Results-Monocytes from healthy female and male donors were obtained from white cell concentrates and allowed to differentiate into macrophages over 10 days. These human monocyte-derived macrophages (MDMs) were exposed to either control (0.1% vol/vol ethanol) or estrogen or progesterone treatment on days 3 through 10. Lipid loading was achieved on days 8 through 10 by incubation with acetylated LDL. Lipid from the MDMs was then extracted for analysis of cholesteryl ester (CE) content. 17␤-Estradiol at both physiological (2 nmol/L) and supraphysiological (20 and 200 nmol/L) concentrations produced a significant reduction in macrophage CE content (88Ϯ3%, 88Ϯ2%, and 85Ϯ4%, respectively; PϽ0.02 compared with control). Physiological and supraphysiological levels of progesterone (2, 10, and 200 nmol/L) produced an even more dramatic reduction in CE content (74Ϯ9%, 56Ϯ10%, and 65Ϯ8%, respectively; PϽ0.002 compared with control). This effect could be abrogated by coincubation with the progesterone receptor antagonist RU486. Neither estrogen nor progesterone produced a reduction in lipid loading in male-donor-derived MDMs. Detailed lipid trafficking studies demonstrated that both estrogen and progesterone altered macrophage uptake and/or processing of modified LDL. Conclusions-Physiological levels of estrogen and progesterone are associated with a female-sex-specific reduction in human macrophage lipid loading, which is consistent with an atheroprotective effect. (Circulation. 1999;100:2319-2325.)

show abstract

Section: Discussionmentioning

confidence: 99%

Estrogen and Progesterone Reduce Lipid Accumulation in Human Monocyte-Derived Macrophages

et al. 1999

View full text Add to dashboard Cite

show abstract

“…After elastica van-Gieson's staining, the neointimal and medial areas in the histological cross-sections were measured morphometrically. 6 The ratio of intima to media was then calculated and used for statistical evaluation.…”

Section: Histological Examinationmentioning

confidence: 99%

Effect of Testosterone on Plaque Development and Androgen Receptor Expression in the Arterial Vessel Wall

et al. 2001

Self Cite

View full text Add to dashboard Cite

Background-Recent studies have suggested that testosterone has a protective effect in the arterial vascular system. However, little is known about the molecular aspects of the mechanism(s) involved in these processes. The aim of the present study was to investigate the effect of testosterone on neointimal plaque development and on the expression of the vascular androgen receptor. Methods and Results-Neointimal plaque formation was induced by endothelial denudation in the aortas of male New Zealand White rabbits. Aortic ring segments were cultured for 21 days after endothelial denudation. Testosterone was applied to the culture medium in different doses. Compared with the non-hormone-treated control group, a significant inhibition of neointimal plaque development (expressed as the intima/media ratio) was found at testosterone concentrations of 10 ng/mL (Pϭ0.037) and 100 ng/mL (Pϭ0.012; intima/media ratios: median of controls, 0.25; median of 10 ng/mL testosterone group, 0.15; median of 100 ng/mL testosterone group, 0.16). Associated with this inhibitory effect on plaque size was a 50% increase of the amount of androgen receptor mRNA in the arterial segments treated with testosterone. Conclusion-The beneficial effects of testosterone on postinjury plaque development underlines, at least in males, the important role of androgens in the vascular system. As our data suggest, the vascular androgen receptor is probably involved in these processes. Further studies are required to characterize the androgen receptor-dependent pathways in the vascular system. Key Words: testosterone Ⅲ receptors, androgen Ⅲ atherosclerosis T he role of androgens in atherogenesis is controversial 1 ; however, in recent years, several authors have found a number of beneficial effects of testosterone, at least in men. Animal studies have documented an inhibitory effect on plaque development in the cholesterol-fed rabbit model, 2,3 whereas in recent clinical investigations, acute hemodynamic effects of testosterone on coronary vasomotion and stress-test induced ischemia were observed. 4,5 Thus far, only limited information is available regarding the possible involvement of arterial androgen receptors in these processes. Thus, the aim of the present study was to investigate, in an experimental model, (1) the dose-dependent effects of testosterone on plaque development, (2) the expression of the androgen receptor in arteries, and (3) possible dose-dependent changes of androgen receptor expression induced by testosterone. Methods Organ Culture SystemTwelve-week-old male New Zealand White rabbits were used for the present study. The rabbits received standard chow without cholesterol (Altromin Inc) and were housed individually (no female rabbits were present). After sacrifice, the abdomen was opened under sterile conditions, and the connective tissue was removed from the aorta. A 3F-Fogarty catheter (Baxter Inc) was inserted below the iliac bifurcation, and endothelial denudation was performed once with the inflated catheter. The aorta was then comp...

show abstract

“…Vascular smooth muscle cells (VSMC) 1 in the normal vessel wall proliferate at a very low frequency. Injury to the endothelium results in the release of mitogens that stimulate quiescent, G 0 /G 1 -arrested VSMC to reenter the cell cycle, replicate DNA, and divide.…”

mentioning

confidence: 99%

“…Injury to the endothelium results in the release of mitogens that stimulate quiescent, G 0 /G 1 -arrested VSMC to reenter the cell cycle, replicate DNA, and divide. VSMC hyperplasia is a key event in the formation of restenotic and atherosclerotic lesions in the vasculature (1,2). Cyclin-dependent kinases (CDKs) are serinethreonine protein kinases that regulate cell cycle progression after forming complexes with and being activated by cyclins (3).…”

mentioning

confidence: 99%

Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Mitogenic Induction of p21Cip1 by Modulating the Protein Kinase Cδ Pathway in Vascular Smooth Muscle Cells

Wakino¹,

Kintscher²,

Liu³

et al. 2001

Journal of Biological Chemistry

View full text Add to dashboard Cite

The cyclin-dependent kinase inhibitor p21Cip1 is upregulated in response to mitogenic stimulation in various cells. PPAR␥ ligands troglitazone (TRO, 10 M) and rosiglitazone (RSG, 10 M) attenuated the induction of p21Cip1 protein by platelet-derived growth factor (PDGF) and insulin without affecting cognate mRNA levels in rat aortic smooth muscle cells (RASMC). The protein kinase C␦ (PKC␦) inhibitor rottlerin also blocked the induction of p21Cip1 protein, whereas the conventional PKC isotype inhibitor Gö 6976 had no effect. Kinetic studies using the protein synthesis inhibitor cycloheximide showed that TRO, RSG, and rottlerin shortened the half-life of p21 Cip1 expression in PDGFtreated RASMC. PPAR␥ ligands enhanced proteintyrosine-phosphatase activity in RASMC, which may be the mechanism for decreased PKC␦ tyrosine phosphorylation and activity. PPAR␥ ligands regulate p21Cip1 at a post-translational level by blocking PKC␦ signaling and accelerating p21Cip1 turnover.Vascular smooth muscle cells (VSMC) 1 in the normal vessel wall proliferate at a very low frequency. Injury to the endothelium results in the release of mitogens that stimulate quiescent, G 0 /G 1 -arrested VSMC to reenter the cell cycle, replicate DNA, and divide. VSMC hyperplasia is a key event in the formation of restenotic and atherosclerotic lesions in the vasculature (1, 2). Cyclin-dependent kinases (CDKs) are serinethreonine protein kinases that regulate cell cycle progression after forming complexes with and being activated by cyclins (3). Mitogenic activation of cyclin D⅐CDK4, cyclin D⅐CDK6, and cyclin E⅐CDK2 during the G 1 phase results in phosphorylation of retinoblastoma gene (Rb) proteins. In its hyperphosphorylated state, Rb functions as a gatekeeper for the G 1 3 S transition by binding and sequestering E2F, a transcription factor that induces the expression of a battery of genes that encode the enzymatic machinery for S phase DNA synthesis. Cyclindependent kinase inhibitors (CDKIs) can negatively regulate the mitogen-induced cascade of G 1 events by inhibiting CDK activity and preventing Rb phosphorylation (3, 4).Consistent with the view that CDKIs are major negative regulators of the cell cycle, overexpression of Cip/Kip family members (p21 Cip1 , p27 Kip1 ) blocks the G 1 exit in VSMC and other cell types (5, 6). Data emerging from recent studies, however, suggest that CDKIs p21Cip1 and p27 Kip1 can also function as positive regulators during the G 1 phase as assembly factors to promote formation of cyclin⅐CDK holoenzyme complexes (3, 7). Such a role for CDKIs may explicate apparent paradoxical observations that p21Cip1 is frequently up-regulated after mitogenic stimulation of quiescent cells (8,9). In rat VSMC cell lines, prevention of mitogen-induced p21 Cip1 expression by antisense oligodeoxynucleotides attenuated both DNA synthesis and cell proliferation (10). We recently reported that ligands for the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR␥) inhibited Rb phosphorylation and G 1 3 S transition in ra...

show abstract

Different Effects of Estrogen and Progesterone on Experimental Atherosclerosis inFemale Versus Male Rabbits

Abstract: Our data suggest that the atheroprotective effect of estrogen is probably due to a mechanism that is present in female rabbits only.

Cited by 71 publications

References 27 publications

Estrogen and Progesterone Reduce Lipid Accumulation in Human Monocyte-Derived Macrophages

Estrogen and Progesterone Reduce Lipid Accumulation in Human Monocyte-Derived Macrophages

Effect of Testosterone on Plaque Development and Androgen Receptor Expression in the Arterial Vessel Wall

Peroxisome Proliferator-activated Receptor γ Ligands Inhibit Mitogenic Induction of p21Cip1 by Modulating the Protein Kinase Cδ Pathway in Vascular Smooth Muscle Cells

Contact Info

Product

Resources

About