RhoA activation in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats

Nobuyuki Moriki, Masaaki Ito, Tetsuya Seko, Yasuko Kureishi, Ryuji Okamoto, Tetsuya Nakakuki, Mariko Kongo, Naoki Isaka, Kozo Kaibuchi, Takeshi Nakano

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Abstract

RhoA is commonly activated in the aorta in various hypertensive models, indicating that RhoA seems to be a molecular switch in hypertension. The molecular mechanisms for RhoA activation in stroke-prone spontaneously hypertensive rats (SHRSP) were here investigated using cultured aortic smooth muscle cells (VSMC). The level of the active form of RhoA was higher in VSMC from SHRSP than in those from Wistar-Kyoto rats (WKY). The phosphorylation level of myosin phosphatase target subunit 1 (MYPT1) at the inhibitory site was also significantly higher in SHRSP, and the phosphorylation levels in both VSMCs were strongly inhibited to a similar extent by treatment with Y-27632, a Rho-kinase inhibitor. The expression levels of RhoA/Rho-kinase related molecules, namely RhoA, Rho-kinase, MYPT1, CPI-17 (inhibitory phosphoprotein for myosin phosphatase) and myosin light chain kinase, were not different between SHRSP and WKY. Valsartan, an angiotensin II (Ang II)- type 1 receptor antagonist, selectively and significantly reduced the RhoA activation in VSMC from SHRSP. The expression levels of the Rho GDP-dissociation inhibitor (RhoGDI) and leukemia-associated Rho-specific guanine nucleotide exchange factor (RhoGEF) did not differ between SHRSP and WKY. In cyclic nucleotide signaling, cyclic GMP (cGMP)-dependent protein kinase Iα (cGKIα) was significantly downregulated in SHRSP cells, although there were no changes in the expression levels of guanylate cyclase β and cyclic AMP (cAMP -dependent protein kinase or the intracellular contents of cGMP and cAMP between the two rat models. These results suggest that the possible mechanisms underlying RhoA activation in VSMC from SHRSP are autocrine/paracrine regulation by Ang II and/or cGKIα downregulation.

Original languageEnglish
Pages (from-to)263-270
Number of pages8
JournalHypertension Research
Volume27
Issue number4
DOIs
Publication statusPublished - 04-2004

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Physiology
  • Cardiology and Cardiovascular Medicine

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    Moriki, N., Ito, M., Seko, T., Kureishi, Y., Okamoto, R., Nakakuki, T., Kongo, M., Isaka, N., Kaibuchi, K., & Nakano, T. (2004). RhoA activation in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats. Hypertension Research, 27(4), 263-270. https://doi.org/10.1291/hypres.27.263