Title: Air pollution exposure potentiates hypertension through reactive oxygen species-mediated activation of Rho/ROCK.
Authors: Sun, Qinghua; Yue, Peibin; Ying, Zhekang; Cardounel, Arturo J; Brook, Robert D; Devlin, Robert; Hwang, Jing-Shiang; Zweier, Jay L; Chen, Lung Chi; Rajagopalan, Sanjay
Published In Arterioscler Thromb Vasc Biol, (2008 Oct)
Abstract: Fine particulate matter <2.5 microm (PM(2.5)) has been implicated in vasoconstriction and potentiation of hypertension in humans. We investigated the effects of short-term exposure to PM(2.5) in the angiotensin II (AII) infusion model.Sprague-Dawley rats were exposed to PM(2.5) 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 PM(2.5) inside the chamber was 79.1+/-7.4 microg/m(3). After AII infusion, mean arterial pressure was significantly higher in PM(2.5)-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 PM(2.5)-AII group. Superoxide (O(2).(-)) production in aorta was increased in the PM(2.5)-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 PM(2.5) 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 O(2)(.-)-mediated mechanism for PM(2.5) and UFP effects.Short-term air pollution exaggerates hypertension through O(2)(.-)-mediated upregulation of the Rho/ROCK pathway.
PubMed ID: 18599801
MeSH Terms: Angiotensin II/administration & dosage; Animals; Antioxidants/pharmacology; Aorta, Thoracic/drug effects; Aorta, Thoracic/enzymology; Biopterin/analogs & derivatives; Biopterin/metabolism; Blood Pressure/drug effects; Cells, Cultured; Disease Models, Animal; Enzyme Inhibitors/pharmacology; Hypertension/chemically induced*; Hypertension/enzymology; Hypertension/physiopathology; Infusion Pumps, Implantable; Inhalation Exposure*; Male; Myosin Light Chains/metabolism; NADPH Oxidases/metabolism; Nitric Oxide Synthase/metabolism; Particle Size; Particulate Matter/toxicity*; Phosphorylation; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species/metabolism*; Signal Transduction/drug effects*; Time Factors; Vasoconstriction/drug effects; rho-Associated Kinases/antagonists & inhibitors; rho-Associated Kinases/genetics; rho-Associated Kinases/metabolism*; rhoA GTP-Binding Protein/metabolism*