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VASCULAR BIOLOGY

PKC mediates anti-proliferative, pro-apoptic effects of testosterone on coronary smooth muscle

¹Department of Biomedical Sciences, ²Dalton Cardiovascular Research Center, ³National Center for Gender Physiology, University of Missouri, Columbia, Missouri; ⁴Intercollege Program in Physiology, The Pennsylvania State University, University Park; and ⁵Resources and ⁶Department of Safety Assessment, Merck Research Laboratories, West Point, Pennsylvania

Submitted 29 March 2007 ; accepted in final form 15 May 2007

Sex hormone status has emerged as an important modulator of coronary physiology and cardiovascular disease risk in both males and females. Our previous studies have demonstrated that testosterone increases protein kinase C (PKC) expression and activity in coronary smooth muscle (CSMC). Because PKC has been implicated in regulation of proliferation and apoptosis in other cell types, we sought to determine if testosterone modulates CSMC proliferation and/or apoptosis through PKC. Porcine CSMC cultures (passages 2–6) from castrated males were treated with testosterone for 24 h. Testosterone (20 and 100 nM) decreased [³H]thymidine incorporation in proliferating CSMC to 59 ± 5.3 and 33.1 ± 4.5% of control. Flow cytometric analysis demonstrated that testosterone induced G₁ arrest in CSMC with a concomitant reduction in the S phase cells. Testosterone reduced protein levels of cyclins D₁ and E and phosphorylation of retinoblastoma protein while elevating levels of p21^cip1 and p27^kip1. There were no significant differences in the levels of cyclins D₃, CDK2, CDK4, or CDK6. Testosterone significantly reduced kinase activity of CDK2 and -6, but not CDK4, -7, or -1. PKC small interfering RNA (siRNA) prevented testosterone-mediated G₁ arrest, p21^cip1 upregulation, and cyclin D₁ and E downregulation. Furthermore, testosterone increased CSMC apoptosis in a dose-dependent manner, which was blocked by either PKC siRNA or caspase 3 inhibition. These findings demonstrate that the anti-proliferative, pro-apoptotic effects of testosterone on CSMCs are substantially mediated by PKC.

androgens; coronary; smooth muscle; cell cycle