Long-term inhibition of RhoA attenuates vascular contractility by enhancing endothelial NO production in an intact rabbit mesenteric artery

Noriko Shiga, Katsuya Hirano, Mayumi Hirano, Junji Nishimura, Hajime Nawata, Hideo Kanaide

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

RhoA plays a critical role in regulating NO production in cultured endothelial cells. To determine its role in in situ endothelial cells, we investigated the effects of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors and a RhoA-binding domain of Rho-kinase (RB) on vascular contractility in the isolated rabbit mesenteric artery. Ex vivo treatment of the strips with 3×10-5 mol/L simvastatin and fluvastatin for ≈24 to 30 hours significantly attenuated the contractile response to phenylephrine and high K+ in the presence of endothelium. The addition of Nω-nitro-L-arginine methyl ester and the removal of endothelium abolished the attenuation of the contractile response. The cotreatment with geranylgeranyl pyrophosphate prevented the statin-induced attenuation of the contractile response, whereas geranylgeranyl transferase inhibitor mimicked the effect of simvastatin. Treatment with simvastatin enhanced the bradykinin-induced endothelium-dependent relaxation in the mesenteric artery, whereas it had no effect on the bradykinin-induced [Ca 2+]i elevation in endothelial cells of the aortic valves. Introduction of RB to the strips using a cell-penetrating peptide of Tat protein (TATHA-RB) attenuated the contractile responses in a NO-dependent manner. However, a Rac1/Cdc42-binding fragment of p21-activated protein kinase, RB without Tat peptide or TATHA-protein A had no effect. The in vivo treatment of rabbit with simvastatin and TATHA-RB attenuated the contractility in a NO-dependent manner. Simvastatin and TATHA-RB significantly upregulated eNOS in the rabbit mesenteric artery. The present study provides the first evidence that RhoA plays a physiological role in suppressing NO production in in situ endothelial cells.

Original languageEnglish
Pages (from-to)1014-1021
Number of pages8
JournalCirculation research
Volume96
Issue number9
DOIs
Publication statusPublished - Mar 13 2005

Fingerprint

Mesenteric Arteries
Simvastatin
Blood Vessels
Rabbits
Endothelial Cells
Endothelium
fluvastatin
Bradykinin
p21-Activated Kinases
Cell-Penetrating Peptides
tat Gene Products
Hydroxymethylglutaryl-CoA Reductase Inhibitors
rho-Associated Kinases
Staphylococcal Protein A
Phenylephrine
Transferases
Aortic Valve
Protein Kinases
Cultured Cells
Oxidoreductases

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Long-term inhibition of RhoA attenuates vascular contractility by enhancing endothelial NO production in an intact rabbit mesenteric artery. / Shiga, Noriko; Hirano, Katsuya; Hirano, Mayumi; Nishimura, Junji; Nawata, Hajime; Kanaide, Hideo.

In: Circulation research, Vol. 96, No. 9, 13.03.2005, p. 1014-1021.

Research output: Contribution to journalArticle

Shiga, Noriko ; Hirano, Katsuya ; Hirano, Mayumi ; Nishimura, Junji ; Nawata, Hajime ; Kanaide, Hideo. / Long-term inhibition of RhoA attenuates vascular contractility by enhancing endothelial NO production in an intact rabbit mesenteric artery. In: Circulation research. 2005 ; Vol. 96, No. 9. pp. 1014-1021.
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