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...

Objective-Matrix metalloproteinases (MMPs) seem to play a prominent role in atherogenesis. Extracellular MMP inducer (EMMPRIN), a cell surface glycoprotein which stimulates MMP synthesis, has recently been detected in human atheroma. We have investigated the influence of oxidized low-density lipoproteins (oxLDLs) on EMMPRIN expression in human coronary artery smooth muscle cells (HCA-SMCs). Methods and Results-OxLDL induced a significant increase of EMMPRIN release into HCA-SMC supernatants and a concomitant decrease of cell-associated EMMPRIN. These effects were antagonized by antioxidants as well as by EDTA and the MMP inhibitor GM6001. Western blot analysis demonstrated that MMP-1 and MMP-2 induce the cleavage of the extracellular domain from cell-associated EMMPRIN. MMP-1 and MMP-2 synthesis was upregulated by oxLDL, and, in addition, we have shown that soluble EMMPRIN, isolated from macrophage supernatants, increased MMP-1 and MMP-2 synthesis in HCA-SMC. Key Words: smooth muscle cells Ⅲ low density lipoproteins Ⅲ matrix metalloproteinases Ⅲ extracellular MMP inducer Ⅲ atherosclerosis D eposition of low-density lipoproteins (LDLs) in the vessel wall and their oxidative modification seem to initiate, or at least accelerate, the atherosclerotic process by several mechanisms, including promotion of foam cell formation, chemotactic effects on monocytes, and mitogenic effects on smooth muscle cells. Recent studies have demonstrated that oxidized LDLs (oxLDLs) increase the expression of matrix metalloproteinases (MMPs) in endothelial cells, monocyte-derived macrophages, and smooth muscle cells [1][2][3] and that MMP expression is enhanced in atherosclerotic plaque tissue. 4 MMPs increase smooth muscle cell migration and proliferation 5,6 and also seem to promote plaque instability by inducing extracellular matrix degradation. 7 Expression of extracellular MMP inducer (EMMPRIN) in human atheroma has been described recently. 8,9 EMMPRIN, also called CD147 or basigin, is a highly glycosylated plasma membrane protein (Ϸ58 kDa) belonging to the immunoglobulin superfamily. EMMPRIN is expressed on several cell types like leukocytes and different tumor cells 10 and stimulates MMP production in fibroblasts and various tumor cells. 11,12 Several studies have shown that cancer cells express significantly higher EMMPRIN levels than normal cells, and it has been proposed that elevated EMMPRIN expression in tumor cells may promote tumor progression by inducing MMP expression in peritumoral stromal cells. In this study, we have demonstrated that EMMPRIN is expressed in cultured human coronary artery smooth muscle cells (HCA-SMCs) and that oxLDL significantly enhanced the release of soluble EMMPRIN as well as MMP-1 and MMP-2 release. In addition, we have shown that MMP-1 and MMP-2 seem to promote the cleavage of soluble EMMPRIN from the cell surface and that soluble EMMPRIN stimulates MMP synthesis in HCA-SMC. Thus our data suggest that oxLDL might induce a circular upregulation of matrix degradation. Conclusion-Our Materials and...

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