on October 21, 2004
Published online before print October 21, 2004, doi: 10.1161/01.ATV.0000148449.92035.3a
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Submitted on June 28, 2004
Accepted on October 12, 2004
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 ;
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.
* To whom correspondence should be addressed. 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 this 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 classic 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.
Key words: protein kinase D • PKC • angiotensin II • angiotensin II receptors • signal transduction
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