Referenced in: none

Automatically associated channels: Cav1.2

Title: PKCdelta mediates testosterone-induced increases in coronary smooth muscle Cav1.2.

Authors: Kamala K Maddali, Donna H Korzick, Darla L Tharp, Douglas K Bowles

Journal, date & volume: J. Biol. Chem., 2005 Dec 30 , 280, 43024-9

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/16243844

Abstract
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 (Cav1.2) in coronary arteries of males. The purpose of the present study was to determine whether testosterone (T) alters coronary protein kinase C delta (PKCdelta) expression and whether PKCdelta plays a role in coronary Cav1.2 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 degrees 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 approximately 2-3-fold increase in PKCdelta protein levels, approximately 1.5-2-fold increase in PKCdelta kinase activity, and localization of PKCdelta toward the plasma membrane and nuclear envelope. PKCdelta protein levels were higher in coronary arteries of intact males compared with intact females. Elimination of endogenous testosterone by castration reduced RCA PKCdelta protein levels, an effect partially (approximately 45%) reversed by exogenous T (castrated males with T replacement). In CSMC, PKC inhibition with either the general PKC inhibitor, cheylerythrine, or the putative PKCdelta inhibitor, rottlerin, completely inhibited the T-mediated increase in coronary Cav1.2 protein levels. Conversely, Go6976, a conventional PKC isoform inhibitor, failed to inhibit T-induced increases in coronary Cav1.2 protein levels. PKCdelta short interference RNA completely blocked T-induced increases in Cav1.2 protein levels in CSMC. These results demonstrate for the first time that 1) endogenous T is a primary modulator of coronary PKCdelta protein and activity in males and 2) T increases Cav1.2 protein expression in a PKCdelta-dependent manner.