Long-term inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo: effect on endothelial NAD(P)H oxidase system.

Abstract

Intracellular signaling pathway mediated by small GTPase Rho and its effector Rho-kinase plays an important role in regulation of vascular smooth muscle contraction and other cellular functions. We have recently demonstrated that Rho-kinase is substantially involved in angiotensin II-induced gene expressions and various cellular responses in vitro. However, it remains to be examined whether Rho-kinase is involved in the angiotensin II-induced cardiovascular hypertrophy in vivo and, if so, what mechanisms are involved. Long-term infusion of angiotensin II for 4 weeks caused hypertrophic changes of vascular smooth muscle and cardiomyocytes in rats. Both changes were significantly suppressed by concomitant oral treatment with fasudil, which is metabolized to a specific Rho-kinase inhibitor, hydroxyfasudil, after oral administration. Angiotensin II caused a perivascular accumulation of macrophages and Rho-kinase activation, both of which were also significantly suppressed by fasudil. Vascular NAD(P)H oxidase expression (nox1, nox4, gp91phox, and p22phox) and endothelial production of superoxide anions were markedly increased by angiotensin II, both of which were also significantly suppressed by fasudil. Thus, fasudil ameliorated the impaired endothelium-dependent relaxations caused by angiotensin II without affecting vasodilator function of vascular smooth muscle. These results provide evidence that Rho-kinase is substantially involved in the angiotensin II-induced cardiovascular hypertrophy in rats in vivo. The suppression of endothelial NAD(P)H oxidase upregulation and resultant superoxide production and the amelioration of endothelial vasodilator function may be involved in this process.

• Authors: Midoriko Higashi, Hiroaki Shimokawa, Tsuyoshi Hattori, Junko Hiroki, Yasushi Mukai, Keiko Morikawa, Toshihiro Ichiki, Shosuke Takahashi, Akira Takeshita
• Journal: Circulation research (Circ Res) Vol. 93 Issue 8 Pg. 767-75 (Oct 17 2003) ISSN: 1524-4571 [Electronic] United States
• PMID: 14500337 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Intracellular Signaling Peptides and Proteins
• Vasoconstrictor Agents
• hydroxyfasudil
• Superoxides
• Angiotensin II
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• NADPH Oxidases
• Protein Serine-Threonine Kinases
• rho-Associated Kinases

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (analogs & derivatives, pharmacology)
• Angiotensin II (toxicity)
• Animals
• Aorta, Thoracic (cytology)
• Cardiomegaly (chemically induced, enzymology, pathology)
• Cell Movement (drug effects)
• Coronary Vessels (pathology)
• Endothelium, Vascular (drug effects, enzymology, physiopathology)
• Enzyme Inhibitors (pharmacology)
• Hypertension (chemically induced)
• Intracellular Signaling Peptides and Proteins
• Macrophages (drug effects, physiology)
• Male
• NADPH Oxidases (metabolism)
• Organ Culture Techniques
• Protein Serine-Threonine Kinases (antagonists & inhibitors, physiology)
• Rats
• Rats, Inbred WKY
• Superoxides (metabolism)
• Vasoconstrictor Agents (toxicity)
• Vasodilation (drug effects)
• rho-Associated Kinases