Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 290, Issue 1, Pages H46-H54Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00769.2005
Keywords
vascular smooth muscle cells; protein kinase C zeta; angiotensin II
Funding
- PHS HHS [19134-29] Funding Source: Medline
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ANG II stimulates phospholipase D (PLD) activity and growth of vascular smooth muscle cells (VSMC). The atypical protein kinase C-zeta ( PKC zeta) plays a central role in the regulation of cell survival and proliferation. This study was conducted to determine the relationship between ANG II- induced activation of PKC zeta and PLD and their implication in VSMC adhesion, spreading, and hypertrophy. ANG II stimulated PKC zeta activity with maximal activation at 30 s followed by a decline in its activity to 45% above basal at 5 min. Inhibition of PKC zeta activity with a myristoylated pseudosubstrate peptide or overexpression of a kinase- inactive form of PKC zeta decreased ANG II- induced PLD activity. Moreover, depletion of PKC zeta with selective antisense oligonucleotides also decreased ANG II- induced PLD activity. Interaction between PLD2 and PKC zeta in VSMC was detected by coimmunoprecipitation. ANG II-induced PLD activity was inhibited by the primary alcohol n-butanol but not the tertiary alcohol t-butanol. The functional significance of PKC zeta and PLD2 in VSMC adhesion, spreading, and hypertrophy was investigated. Inhibition of PKC zeta and PLD2 activity or expression attenuated VSMC adhesion to collagen I and ANG II-induced cell spreading and hypertrophy. These results demonstrate that ANG II-induced PLD activation is regulated by PKC zeta and suggest a crucial role of PKC zeta-dependent PLD2 in VSMC functions such as adhesion, spreading, and hypertrophy, which are associated with the pathogenesis of atherosclerosis and malignant hypertension.
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