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Am. J. Respir. Cell Mol. Biol., Volume 25, Number 5, November, 2001 628-635

Rho-Kinase Activation Is Involved in Hypoxia-Induced Pulmonary Vasoconstriction

Zhiqian Wang, Najia Jin, Supriya Ganguli, Darl R. Swartz, Liang Li, and Rodney A. Rhoades

Departments of Cellular/Integrative Physiology, and Anatomy/Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana; and Department of Chemistry, Indiana State University, Terre Haute, Indiana

Rho-associated serine/threonine kinase (Rho-kinase) is a downstream effector of small GTPase RhoA that has recently been shown to play an important role in regulating smooth muscle contraction. The present study investigated the role of Rho/ Rho-kinase in hypoxia-induced pulmonary vasoconstriction (HPV). Small pulmonary resistance vessels and cultured pulmonary arterial smooth muscle cells (PASMCs) from the rat were used. PASMCs exposed to hypoxia (PO2 = 26 ± 2 mm Hg) showed a significant increase in Rho-kinase activity. Exposure to hypoxia for 20, 40, 60, 90, and 120 min also resulted in a significant increase in myosin light chain (MLC) phosphorylation at all time points in PASMCs. Hypoxia-induced MLC phosphorylation was inhibited by Y-27632 (a Rho-kinase inhibitor), exoenzyme C3 (a specific Rho inhibitor), or toxin B (an inhibitor for Rho proteins). In addition, hypoxia-induced Rho-kinase activation was blocked by C3 and toxin B. Small rat intrapulmonary arterial rings, which were made hypoxic (PO2 = 30 ± 3 mm Hg), showed a slow sustained contraction, and Y-27632 caused a significant relaxation during the sustained phase of HPV in a concentration-dependent manner. In summary, the data show that Rho-kinase is activated by hypoxia in PASMCs, and Rho/Rho-kinase is functionally linked to hypoxia-induced MLC phosphorylation and plays a role in the sustained phase of HPV.

Abbreviations: Dulbecco's modified Eagle's medium, DMEM; dithiothreitol, DTT; fetal bovine serum, FBS; hypoxic pulmonary vasoconstriction, HPV; myosin light chain kinase, MLC; pulmonary arterial smooth muscle cells, PASMCs; partial pressure of oxygen, PO2; Rho-associated serine/ threonine kinase, Rho-kinase; sodium dodecyl sulfate, SDS; trichloroacetic acid, TCA.




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