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Cardiovascular Research Advance Access [Accepted Manuscript] published online on March 10, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp084
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Salicylates dilate blood vessels through inhibiting PYK2-mediated RhoA/Rho-kinase activation

Zhekang Ying, Ph.D.1, Fernanda R.C. Giachini, Ph.D.1,2, Rita C. Tostes, Ph.D.1,2 and R. Clinton Webb, Ph.D.1

1 Department of Physiology, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912, U.S.A
2 Pharmacology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, SP, Brazil

Correspondence should be addressed to: Zhekang Ying, Davis Heart & Lung Research Institute, Ohio State University, BLDG BRT/RM350, 460 W 12th Avenue, Columbus, Ohio, 43210, Tel: 001-614-247-2531, Fax: 001-614-293-5614, zhekang.ying{at}osumc.edu

Aims: Compared to other non-steroid anti-inflammatory drugs, aspirin is not correlated to hypertension. It has been shown that aspirin has unique vasodilator action in vivo, offering an explanation for the unique blood pressure effect of aspirin. In the present study, we investigate the mechanism whereby salicylates (aspirin and sodium salicylate) dilate blood vessels.

Methods: Rat aortic or mesenteric arterial rings were used to test the vascular effect of salicylates and other non-steroid anti-inflammatory drugs. RhoA translocation and the phosphorylation of MYPT1, the regulatory subunit of myosin light chain phosphatase (MLCP), were measured by western blot, as evidence for RhoA/Rho-kinase activation.

Results: Salicylates, but not other non-steroid anti-inflammatory drugs, relaxed contraction induced by most tested constrictors except for calyculin A, indicating that RhoA/Rho-kinase-mediated calcium sensitization is involved. The involvement of RhoA/Rho-kinase in vasodilation by salicylates was confirmed by measurements of RhoA translocation and MYPT1 phosphorylation. The calculated half maximal inhibitory concentration (IC50) of vasodilation was apparently higher than that of cyclo-oxygenase inhibition, but comparable to that of proline-rich tyrosine kinase 2 (PYK2) inhibition. Over-expression of PYK2 induced RhoA translocation and MYPT1 phosphorylation, and these effects were markedly inhibited by sodium salicylate treatment. Consistent with the ex vitro vascular effects, sodium salicylate acutely decreased blood pressure in SHR but not WKY rats.

Conclusions: Salicylates dilate blood vessels through inhibiting PYK2-mediated RhoA/Rho-kinase activation and thus lower blood pressure.

KEYWORDS G proteins; Contractile function; Smooth muscle; Hypertension

Time for primary review: 25 Days

Classifications. Experimental, Vasculature, Cellular, Molecular biology


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