Rationale: Pulmonary vascular thrombosis and thrombotic arteriopathy are common pathological findings in pulmonary arterial hypertension. Thrombin may thus play an important role in the pathogenesis and pathophysiology of pulmonary arterial hypertension. Objectives: The present study aimed to elucidate the contractile effect of thrombin in the pulmonary artery and clarify its underlying mechanisms. Methods: The changes in cytosolic Ca2+ concentrations ([Ca2+]i), 20-kD myosin light chain (MLC20) phosphorylation, and contraction were monitored in the isolated porcine pulmonary artery. The production of reactive oxygen species (ROS) was evaluated by fluorescence imaging. Measurements and Main Results: In the presence of extracellular Ca2+, thrombin induced a sustained contraction accompanied by an increase in [Ca2+]i and the phosphorylation of MLC20. In the absence of extracellular Ca2+, thrombin induced a contraction without either [Ca2+]i elevation or MLC20 phosphorylation. This Ca2+- and MLC20 phosphorylation-independent contraction was mimicked by hydrogen peroxide and inhibited by N-acetyl cysteine. Fluorescence imaging revealed thrombinto induce the production of ROS. A Rho-kinase inhibitor, Y27632, inhibited not only the thrombin-induced Ca2+- and MLC20 phosphorylation-dependent contraction, but also the Ca2+- and MLC20 phosphorylation-independent contraction and the ROS production. These effects of thrombin were mimicked by a proteinase-activated receptor 1 (PAR1)-activating peptide. Conclusions: This study elucidated the Ca2+- and MLC20 phosphorylation-independent ROS-mediated noncanonical mechanism as well as Ca2+- and MLC20 phosphorylation-dependent canonical mechanism that are involved in the thrombin-induced PAR1-mediated pulmonary vasoconstriction. Rho-kinase was suggested to play multiple roles in the development of thrombin-induced pulmonary vasoconstriction.
|Number of pages||10|
|Journal||American Journal of Respiratory and Critical Care Medicine|
|Publication status||Published - Dec 1 2010|
All Science Journal Classification (ASJC) codes
- Pulmonary and Respiratory Medicine
- Critical Care and Intensive Care Medicine