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Air pollution exposure potentiates hypertension through reactive oxygen species-mediated activation of Rho/ROCK
Sun, Q., P. Yue, A. J. Cardounel, R. D. Brook, D. Heat, R. B. DEVLIN, J. HWANG, J. L. Zwier, L. C. Chen, AND S. Rajagoplan. Air pollution exposure potentiates hypertension through reactive oxygen species-mediated activation of Rho/ROCK. Arteriosclerosis, Thrombosis, and Vascular Biology. Lippincott Williams & Wilkins, Philadelphia, PA, 28(10):1760-1766, (2008).
OBJECTIVE: Fine particulate matter <2.5 microm (PM2.5) has been implicated in vasoconstriction and potentiation of hypertension in humans. We investigated the effects of short-term exposure to PM2.5 in the angiotensin II (AII) infusion model. METHODS AND RESULTS: Sprague-Dawley rats were exposed to PM2.5 or filtered air (FA) for 10 weeks. At week 9, minipumps containing AII were implanted and the responses studied over a week. Mean concentration of PM2.5 inside the chamber was 79.1+/-7.4 microg/m(3). After AII infusion, mean arterial pressure was significantly higher in PM2.5-AII versus FA-AII group. Aortic vasoconstriction to phenylephrine was potentiated with exaggerated relaxation to the Rho-kinase (ROCK) inhibitor Y-27632 and increase in ROCK-1 mRNA levels in the PM2.5_AII group. Superoxide (O2(.-)) production in aorta was increased in the PM2.5-AII compared to the FA group, inhibitable by apocynin and L-NAME with coordinate upregulation of NAD(P)H oxidase subunits p22(phox) and p47(phox) and depletion of tetrahydrobiopterin. In vitro exposure to ultrafine particles (UFP) and PM2.5 was associated with an increase in ROCK activity, phosphorylation of myosin light chain, and myosin phosphatase target subunit (MYPT1). Pretreatment with the nonspecific antioxidant N-Acetylcysteine and the Rho kinase inhibitors (Fasudil and Y-27632) prevented MLC and MYPT-1 phosphorylation by UFP suggesting a O2(.-)-mediated mechanism for PM2.5 and UFP effects. CONCLUSIONS: Short-term air pollution exaggerates hypertension through O2(.-)-mediated upregulation of the Rho/ROCK pathway.
Record Details:Record Type: DOCUMENT (JOURNAL/PEER REVIEWED JOURNAL)
Organization:U.S. ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
NATIONAL HEALTH AND ENVIRONMENTAL EFFECTS RESEARCH LAB
HUMAN STUDIES DIVISION
CLINICAL RESEARCH BRANCH