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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 PKCδ-specific inhibitor, blocks PKD activation suggests that PKCδ, 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 PKCδ, but neither the dominant-negative form of PKCε nor PKCζ, inhibits PKD activation. These results further substantiate the finding that Ang II–induced PKD activation is mediated by PKCδ. 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 PKCδ in living cells. These data may provide new insights into molecular mechanisms involved in Ang II–induced physiological and pathological events.

arteriosclerosis, thrombosis, and vascular biology

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