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(Hypertension. 2001;37:574.)
© 2001 American Heart Association, Inc.

Scientific Contributions

p38 MAP Kinase Regulates Vascular Smooth Muscle Cell Collagen Synthesis by Angiotensin II in SHR But Not in WKY

Rhian M. Touyz; Gang He; Mohammed El Mabrouk; Ernesto L. Schiffrin

From the Multidisciplinary Research Group on Hypertension, Clinical Research Institute of Montreal (Canada).

Correspondence to R.M. Touyz, MD, PhD, Clinical Research Institute of Montreal, 110 Pine Ave W, Montreal, H2W 1R7, Canada. E-mail touyzr{at}ircm.qc.ca

Vascular remodeling in hypertension is associated with cell growth and increased deposition of extracellular matrix components, particularly collagen. Mechanisms underlying these processes are unclear, but MAP kinases, particularly ERK1/2 and p38 MAP kinase, may be important. We studied the role of ERK1/2 and p38 MAP kinase in vascular smooth muscle cell (VSMC) collagen synthesis and growth mediated by angiotensin (Ang) II in spontaneously hypertensive rats (SHR). Cultured mesenteric VSMC from Wistar-Kyoto rats and SHR were used. Phosphorylation of ERK1/2 and p38 MAP kinase were assessed by Western blots with phosphospecific antibodies. Ang II–stimulated DNA and collagen synthesis were determined by measuring incorporation of ³H-thymidine and ³H-proline, respectively. mRNA expression of procollagen I and III was determined by reverse transcription–polymerase chain reaction. Ang II increased ERK1/2 and p38 MAP kinase phosphorylation. Responses were augmented in SHR. Effects were inhibited by irbesartan, a selective AT₁ antagonist, but not by PD123319, a selective AT₂ blocker. Ang II stimulated ³H-thymidine and ³H-proline incorporation. These actions were enhanced 2- to 3-fold in SHR. PD98059, selective inhibitor of the ERK1/2 pathway, attenuated Ang II–induced growth and collagen effects and normalized responses in SHR. SB212190, a selective p38 MAP kinase inhibitor, did not alter Ang II–elicited DNA synthesis but reduced collagen production and mRNA expression of procollagen I and III in SHR. These data demonstrate that (1) Ang II–mediated activation of p38 and ERK1/2 is increased in SHR, (2) augmented growth responses are generated by ERK1/2-dependent, p38 MAP kinase-independent pathways, and (3) p38 MAP kinase influences Ang II–induced collagen production in SHR but not in Wistar-Kyoto rats. These results indicate differential roles of ERK1/2 and p38 MAP kinase in AT₁-stimulated VSMC growth and collagen production, which may contribute to vascular remodeling in hypertension.

Key Words: kinase • renin-angiotensin system • hypertrophy • arteries • hypertension, arterial

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