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J. Biol. Chem., Vol. 280, Issue 52, 43024-43029, December 30, 2005

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PKC Mediates Testosterone-induced Increases in Coronary Smooth Muscle Ca_v1.2^*

Kamala K. Maddali, Donna H. Korzick, Darla L. Tharp, and Douglas K. Bowles¶||1

From the Department of Biomedical Sciences, ^¶Dalton Cardiovascular Research Center, ^||National Center for Gender Physiology, University of Missouri, Columbia, Missouri 65211 and Department of Kinesiology and Program in Physiology, The Pennsylvania State University, University Park, Pennsylvania 16802

Sex hormones have emerged as important modulators of cardiovascular physiology and pathophysiology. Our previous studies demonstrated that testosterone increases expression and activity of L-type, voltage-gated calcium channels (Ca_v1.2) in coronary arteries of males. The purpose of the present study was to determine whether testosterone (T) alters coronary protein kinase C (PKC) expression and whether PKC plays a role in coronary Ca_v1.2 expression. For in vitro studies, porcine right coronary arteries (RCA) and post-confluent (passages 3-6) 5-day, serum-restricted coronary smooth muscle cell cultures (CSMC) were incubated in the presence and absence of T or dihydrotestosterone (10 and 100 nM) for 18 h at 37 °C in a humidified chamber. For sex and endogenous testosterone-dependent effects, RCA were obtained from intact males, castrated males, castrated males with T replacement, and intact females. In vitro T and dihydrotestosterone caused an 2-3-fold increase in PKC protein levels, 1.5-2-fold increase in PKC kinase activity, and localization of PKC toward the plasma membrane and nuclear envelope. PKC protein levels were higher in coronary arteries of intact males compared with intact females. Elimination of endogenous testosterone by castration reduced RCA PKC protein levels, an effect partially (45%) reversed by exogenous T (castrated males with T replacement). In CSMC, PKC inhibition with either the general PKC inhibitor, cheylerythrine, or the putative PKC inhibitor, rottlerin, completely inhibited the T-mediated increase in coronary Ca_v1.2 protein levels. Conversely, Go6976, a conventional PKC isoform inhibitor, failed to inhibit T-induced increases in coronary Ca_v1.2 protein levels. PKC short interference RNA completely blocked T-induced increases in Ca_v1.2 protein levels in CSMC. These results demonstrate for the first time that 1) endogenous T is a primary modulator of coronary PKC protein and activity in males and 2) T increases Ca_v1.2 protein expression in a PKC-dependent manner.

Received for publication, August 19, 2005 , and in revised form, October 20, 2005.

^* This study was supported by NHLBI, National Institutes of Health Grant HL071574 and by the National Aeronautics and Space Administration. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: E102 Veterinary Medicine, University of Missouri, Columbia, MO 65211. Tel.: 573-882-7193; Fax: 573-884-6890; E-mail: BowlesD{at}missouri.edu.

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