Involvement of Rho-kinase in angiotensin II-induced hypertrophy of rat vascular smooth muscle cells

Angiotensin II (Ang II) is now believed to play a critical role in the path ogenesis of hypertrophy and/or hyperplasia of vascular smooth muscle cells (VSMCs). Several G(i)- and G(q)-coupled receptors, including the Ang II typ e 1 (AT(1)) receptor, activate Rho and Rho-associated kinase in Swiss 3T3 c ells and cardiac myocytes. However, little is known about the role of Rho-k inase in Ang II-induced vascular hypertrophy in VSMCs. In the present study , we explored the role of Rho and Rho-kinase in Ang II-induced protein synt hesis in VSMCs. In unstimulated cells, RhoA was observed predominantly in t he cytosolic fraction, but it was translocated in part to the particulate f raction in response to Ang II (100 nmol/L). This effect was completely bloc ked by the AT(1) receptor blocker candesartan but not by the Ang II type 2 (AT(2)) receptor antagonist PD123319. Botulinum C-3 exoenzyme, which inacti vated RhoA, attenuated Ang II-induced [H-3]leucine incorporation. The speci fic Rho-kinase inhibitor, Y-27632, dose-dependently abolished Ang II-induce d protein synthesis and also suppressed Ang II-induced c-fos mRNA expressio n. On the other hand, Y-27632 had no effect on Ang II-stimulated phosphoryl ation of p70 S6 kinase and extracellular signal-regulated kinase 1/2, which are reported to be involved in Ang II-induced protein synthesis, nor had i t any effect on the Ang II-induced phosphorylation of PHAS-I, a heat- and a cid-stable eIF-4E-binding protein. The phosphorylation of PHAS-I is regulat ing for translation initiation. These observations suggest that the Rho, Rh o-kinase, and c-fos pathways may play a role in Ang II-induced hypertrophic changes of VSMCs through a novel pathway.