Journal
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
Volume 287, Issue 4, Pages H1495-H1500Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.01006.2003
Keywords
myosin light chain phosphatase; smooth muscle contraction; antioxidants
Funding
- NHLBI NIH HHS [HL 71138, HL 18575] Funding Source: Medline
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Evidence indicates that both the Rho/ Rho kinase signaling pathway and reactive oxygen species (ROS) such as superoxide and H2O2 are involved in the pathogenesis of hypertension. This study aimed to determine whether ROS-induced vascular contraction is mediated through activation of Rho/ Rho kinase. Rat aortic rings ( endothelium denuded) were isolated and placed in organ chambers for measurement of isometric force development. ROS were generated by a xanthine (X)-xanthine oxidase (XO) mixture. The antioxidants tempol ( 3 mM) and catalase ( 1,200 U/ml) or the XO inhibitor allopurinol (400 muM) significantly reduced X/XO-induced contraction. A Rho kinase inhibitor, (+)-(R)-trans-4-(1-aminoethyl- N-4-pyridil) cyclohexanecarboxamide dihydrochloride (Y-27632), decreased the contraction in a concentration-dependent manner; however, the Ca2+-independent protein kinase C inhibitor rottlerin did not have an effect on X/XO-induced contraction. Phosphorylation of the myosin light chain phosphatase target subunit (MYPT1) was increased by ROS, and preincubation with Y-27632 blocked this increased phosphorylation. Western blotting for cytosolic and membrane-bound fractions of Rho showed that Rho was increased in the membrane fraction by ROS, suggesting activation of Rho. These observations demonstrate that ROS-induced Ca2+ sensitization is through activation of Rho and a subsequent increase in Rho kinase activity but not Ca2+-independent PKC.
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