Hypoxia Inhibits Myosin Phosphatase in Pulmonary Arterial Smooth Muscle Cells: Role of Rho-Kinase

• Published in: American journal of respiratory cell and molecular biology Vol. 29; no. 4; pp. 465 - 471
• Main Authors: Wang, Zhiqian, Lanner, M. Carita, Jin, Najia, Swartz, Darl, Li, Liang, Rhoades, Rodney A
• Format: Journal Article
• Language: English
• Published: United States Am Thoracic Soc 01-10-2003; American Thoracic Society
• Subjects: Animals; Cells, Cultured; Enzyme Inhibitors - pharmacology; Hypoxia - enzymology; Hypoxia - physiopathology; Intracellular Signaling Peptides and Proteins; Lung - blood supply; Lung - physiopathology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - enzymology; Myosin-Light-Chain Phosphatase; Myosins - metabolism; Phosphoprotein Phosphatases - metabolism; Phosphorylation - drug effects; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Pulmonary Artery - drug effects; Pulmonary Artery - enzymology; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; Signal Transduction - drug effects; Signal Transduction - physiology; Stress Fibers - drug effects; Stress Fibers - metabolism; Up-Regulation - drug effects; Up-Regulation - physiology; Vasoconstriction - drug effects; Vasoconstriction - physiology
• ISSN: 1044-1549; 1535-4989
• DOI: 10.1165/rcmb.2002-0157OC

Rho-kinase was recently found to phosphorylate the myosin-binding subunit (MBS) of myosin phosphatase (MP) and to regulate MP activity. Although myosin light chain (MLC) phosphorylation in pulmonary arterial smooth muscle cells (PASMCs) is thought to be the cellular/molecular basis for hypoxic pulmonary vasoconstriction (HPV), very little is known about the role that Rho-kinase/MP plays in HPV. Rat PASMCs were cultured and made hypoxic (PO2 = 23 +/- 2 mm Hg). Cells exposed to normoxia (PO2 approximately 148 mm Hg) served as controls. PASMCs exposed to hypoxia showed a significant increase in MLC and MBS phosphorylation, and a significant decrease in MP activity. Rho-kinase inhibitors (HA1077 or Y-27632) blocked hypoxia-induced MP inactivation and inhibited the hypoxia-induced MLC phosphorylation. Hypoxia was also found to induce stress fiber formation and actin polymerization in cultured PASMCs. In summary, these data show that MP inhibition in PASMCs is linked to activation of Rho-kinase, and that hypoxia inhibits the MP signaling pathway via Rho-kinase.