Submitted on December 8, 2008
Revised on February 23, 2009
Accepted on March 2, 2009
Air Pollution and Cardiac Remodeling: A Role For RhoA/Rho-kinase
Zhekang Ying1, Peibin Yue2, Xiaohua Xu2, Mianhua Zhong3, Qinghua Sun2, Michael Mikolaj2, Aixia Wang2, Robert D Brook4, Lung Chi Chen3, and Sanjay Rajagopalan5*
1 Ohio State University
2 the Ohio State University
3 New York University School of Medicine
4 University of Michigan Health Systems
5 University of Ohio
* To whom correspondence should be addressed. E-mail: Sanjay.Rajagopalan{at}osumc.edu.
Objectives Exposure to ambient air pollution has been associated with increases in blood pressure. We had previously demonstrated activation of the Rho/ROCK pathway in experimental hypertension in rats. In this investigation we evaluated the effects of particulate matter <2.5µ (PM2.5) exposure on cardiovascular responses and remodeling and tested the effect of Rho-kinase inhibition on these effects. Methods C57BL/6 mice were exposed to concentrated ambient PM2.5 or filtered air (FA) for 12 weeks, followed by a 14 day angiotensin II (AII) infusion in conjunction with fasudil, a Rho-kinase antagonist or placebo treatment. Blood pressure was monitored followed by analysis of vascular function and ventricular remodeling indices. Results PM2.5 exposure potentiated AII induced hypertension, and this effect was abolished by fasudil treatment. Cardiac and vascular RhoA activation was enhanced by PM2.5 exposure along with increased expression of the guanine exchange factors, PDZ-RhoGEF and p115 RhoGEF in PM2.5 exposed mice. Parallel with increased RhoA activation, PM2.5 exposure increased AII induced cardiac hypertrophy and collagen deposition, with these increases being normalized by fasudil treatment. Conclusion PM2.5 potentiates cardiac remodeling in response to AII through RhoA/Rho-kinase dependent mechanisms. These findings have implications for chronic cardiovascular health effects of air pollution.
