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

D. K. Bowles, K. K. Maddali, V. C. Dhulipala, D. H. Korzick

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30 Scopus citations


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) δ expression and activity in coronary smooth muscle (CSMC). Because PKCδ 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 PKCδ. 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 p21cip1 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. PKCδ 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 PKCδ siRNA or caspase 3 inhibition. These findings demonstrate that the anti-proliferative, proapoptotic effects of testosterone on CSMCs are substantially mediated by PKCδ.

Original languageEnglish (US)
Pages (from-to)C805-C813
JournalAmerican Journal of Physiology - Cell Physiology
Issue number2
StatePublished - Aug 2007

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cell Biology


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