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(Hypertension. 2003;41:794.)
© 2003 American Heart Association, Inc.

Scientific Contributions

PKC- Mediates Norepinephrine-Induced Phospholipase D Activation and Cell Proliferation in VSMC

Jean-Hugues Parmentier; Philip Smelcer; Zoran Pavicevic; Edin Basic; Azra Idrizovic; Anne Estes; Kafait U. Malik

From the Department of Pharmacology and Vascular Biology Center of Excellence, College of Medicine, The University of Tennessee Health Science Center, Memphis.

Correspondence to Kafait U. Malik, PhD, DSc, Professor of Pharmacology, College of Medicine, The University of Tennessee, Memphis, 874 Union Ave, Memphis, TN 38163. E-mail kmalik{at}utmem.edu

Norepinephrine (NE) stimulates phospholipase D (PLD) activity and cell proliferation in vascular smooth muscle cells (VSMCs). The objective of this study was to determine the contribution of PKC- to NE-induced PLD activation and cell proliferation in VSMCs. PLD activity was measured by the formation of [³H]phosphatidylethanol in VSMCs labeled with [³H]oleic acid and exposed to ethanol. A high basal PLD activity was detected, and NE increased PLD activity over basal by 70%. This increase was abolished by the broad-range PKC inhibitor Ro 31-8220 (1 µmol/L, 30 minutes) and myristoylated PKC- pseudosubstrate peptide inhibitor (25 µmol/L, 1 hour). Transfection of VSMCs with PKC- antisense, but not sense, oligonucleotides, which reduced PKC- protein level and basal PLD activity, caused a 92% decrease in NE-induced PLD activation. NE-induced increase in PLD activity was also reduced by 61% in cells transfected with kinase-deficient FLAG-T410A-PKC- plasmid but not in those transfected with wild-type PKC-. NE increased immunoprecipitable PKC- activity and phosphorylation, reaching a maximum at 2 and 5 minutes, respectively. NE-induced increase in PKC- activity was inhibited by Ro 31-8220 and by the pseudosubstrate inhibitor. Treatment of VSMCs for 48 hours with PKC- antisense, but not sense, oligonucleotides also inhibited basal and NE-stimulated cell proliferation by 54% and 57%, respectively, as measured by [³H]thymidine incorporation. The inhibitor of PLD activity n-butanol, but not its inactive analog tert-butanol, also reduced the basal and blocked NE-induced cell proliferation. These data suggest that PKC- mediates PLD activation and cell proliferation elicited by NE in rabbit VSMCs.

Key Words: phospholipase D • norepinephrine • muscle, smooth, vascular • protein kinases • cell proliferation

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