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Cardiovascular Research Advance Access first published online on March 10, 2009
This version [Corrected Proof] published online on March 27, 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 Ying1,*, Fernanda R.C. Giachini1,2, Rita C. Tostes1,2 and Robert Clinton Webb1

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

* Corresponding author. Davis Heart and Lung Research Institute, Ohio State University, BLDG BRT/RM350, 460 W 12th Avenue, Columbus, OH 43210, USA. Tel: +1 614 247 2531; fax: +1 614 293 5614; E-mail address: zhekang.ying{at}osumc.edu or yingzhekang{at}hotmail.com

Aims: Compared with other non-steroid anti-inflammatory drugs (NSAIDs), 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 and results: Rat aortic or mesenteric arterial rings were used to test the vascular effect of salicylates and other NSAIDs. RhoA translocation and the phosphorylation of MYPT1, the regulatory subunit of myosin light chain phosphatase, were measured by western blot, as evidenced for RhoA/Rho-kinase activation. Salicylates, but not other NSAIDs, 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 cyclooxygenase 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 spontaneous hypertensive rats but not in Wistar Kyoto rats.

Conclusion: 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


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