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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:2271.)
© 2004 American Heart Association, Inc.

Vascular Biology

Angiotensin II–Induced Protein Kinase D Activation Is Regulated by Protein Kinase C and Mediated via the Angiotensin II Type 1 Receptor in Vascular Smooth Muscle Cells

Mingqi Tan; Xuemin Xu; Motoi Ohba; Mei-Zhen Cui

From the Department of Pathobiology (M.T., X.X., M.-Z.C.), the University of Tennessee, Knoxville; and the Institute of Molecular Oncology (M.O.), Showa University, Shinagawa-ku, Tokyo, Japan.

Correspondence to Mei-Zhen Cui, PhD, Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, 2407 River Dr, Knoxville, TN 37996. E-mail cuim{at}utk.edu

Objective— Angiotensin II (Ang II), through its specific signaling cascades, exerts multiple effects on vascular smooth muscle cells (SMCs). It has been shown that Ang II stimulates activation of protein kinase D (PKD), a member of a new class of serine–threonine kinases. However, little is known regarding the upstream cascade of the intracellular signaling that leads to PKD activation. In the present study, we investigated upstream molecules that mediate Ang II–induced PKD activation in SMCs.

Methods and Results— Protein kinase C (PKC) inhibitors completely block Ang II–induced PKD activation, and pretreatment with phorbol 12,13-dibutyrate downregulates Ang II–induced PKD activation, indicating that classical or novel isoforms of PKC mediate Ang II–induced PKD activation. Furthermore, the finding that rottlerin, a PKC-specific inhibitor, blocks PKD activation suggests that PKC, a member of novel PKCs, mediates Ang II–induced PKD activation. By using dominant-negative approaches, our results demonstrate that expression of the dominant-negative PKC, but neither the dominant-negative form of PKC nor PKC, inhibits PKD activation. These results further substantiate the finding that Ang II–induced PKD activation is mediated by PKC. Moreover, using selective Ang II receptor antagonists, our data show that the Ang II type 1 (AT1) receptor but not the AT2 mediates Ang II–stimulated PKD activation.

Conclusions— This study reveals for the first time that Ang II–induced PKD activation is mediated via AT1 and regulated by PKC in living cells. These data may provide new insights into molecular mechanisms involved in Ang II–induced physiological and pathological events.

The results of our study reveal for the first time that Ang II–induced PKD activation is mediated via AT1 and regulated by PKC in living cells. These data may provide new insights into molecular mechanisms involved in Ang II–induced physiological and pathological events.

Key Words: protein kinase D • PKC • angiotensin II • angiotensin II receptors • signal transduction

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