Published Online
on January 7, 2008

A more recent version of this article appeared on February 1, 2008

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Submitted on September 13, 2007
Revised on September 30, 2007

Novel Role of Protein Kinase C- Tyr³¹¹ Phosphorylation in Vascular Smooth Muscle Cell Hypertrophy by Angiotensin II

Hidekatsu Nakashima; Gerald D. Frank; Heigoro Shirai; Akinari Hinoki; Sadaharu Higuchi; Haruhiko Ohtsu; Kunie Eguchi; Archana Sanjay; Mary E. Reyland; Peter J. Dempsey; Tadashi Inagami; and Satoru Eguchi^*

From the Cardiovascular Research Center and Department of Physiology (H.N., H.S., A.H., S.H., H.O., K.E., S.E.) and Department of Anatomy and Cell Biology (A.S.), Temple University School of Medicine, Philadelphia, Pa; the Department of Biochemistry (G.D.F., T.I.), Vanderbilt University School of Medicine, Nashville, Tenn; the Department of Craniofacial Biology, School of Dentistry, and Department Cell and Developmental Biology, School of Medicine (M.E.R.), University of Colorado Health Science Center, Aurora; and the Departments of Pediatrics and Molecular and Integrative Physiology (P.J.D.), University of Michigan, Ann Arbor.

^* To whom correspondence should be addressed. E-mail: seguchi{at}temple.edu.

Abstract—We have shown previously that activation of protein kinase C- (PKC) is required for angiotensin II (Ang II)–induced migration of vascular smooth muscle cells (VSMCs). Here, we have hypothesized that PKC phosphorylation at Tyr³¹¹ plays a critical role in VSMC hypertrophy induced by Ang II. Immunoblotting was used to monitor PKC phosphorylation at Tyr³¹¹, and cell size and protein measurements were used to detect hypertrophy in VSMCs. PKC was rapidly (0.5 to 10.0 minutes) phosphorylated at Tyr³¹¹ by Ang II. This phosphorylation was markedly blocked by an Src family kinase inhibitor and dominant-negative Src but not by an epidermal growth factor receptor kinase inhibitor. Ang II-induced Akt phosphorylation and hypertrophic responses were significantly enhanced in VSMCs expressing PKC wild-type compared with VSMCs expressing control vector, whereas the enhancements were markedly diminished in VSMCs expressing a PKC Y311F mutant. Also, these responses were significantly inhibited in VSMCs expressing kinase-inactive PKC K376A compared with VSMCs expressing control vector. From these data, we conclude that not only PKC kinase activation but also the Src-dependent Tyr³¹¹ phosphorylation contributes to Akt activation and subsequent VSMC hypertrophy induced by Ang II, thus signifying a novel molecular mechanism for enhancement of cardiovascular diseases induced by Ang II.

Key words: angiotensin II • AT₁ receptor • signal transduction • protein kinase C • Src • hypertrophy • vascular smooth muscle cells

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