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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:949.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Plasmin Induces Endothelium-Dependent Nitric Oxide–Mediated Relaxation in the Porcine Coronary Artery

Tetsuhiro Fujiyoshi; Katsuya Hirano; Mayumi Hirano; Junji Nishimura; Shosuke Takahashi; Hideo Kanaide

From the Division of Molecular Cardiology (T.F., K.H., M.H., J.N., H.K.), Research Institute of Angiocardiology; Department of Anesthesiology and Critical Care (S.T.), Graduate School of Medical Sciences; and Kyushu University, 21st Century Centers of Excellence Program on Lifestyle-Related Diseases (H.K.), Kyushu University, Fukuoka, Japan.

Correspondence to Hideo Kanaide, MD, PhD, Professor, Division of Molecular Cardiology, Research Institute of Angiocardiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail kanaide{at}molcar.med.kyushu-u.ac.jp

Objective— Plasmin is a key enzyme in fibrinolysis. We attempted to determine the possible role of plasmin in the regulation of vascular tone, while also investigating the mechanism of plasmin-induced vasorelaxation.

Methods and Results— In porcine coronary artery, plasmin induced an endothelium-dependent relaxation. This relaxing effect was mostly abolished by a proteinase inhibitor, a plasmin inhibitor, or a nitric oxide (NO) synthase inhibitor. The preceding stimulation with plasmin significantly inhibited the subsequent relaxation induced by thrombin but not that induced by proteinase-activated receptor-1–activating peptide. The relaxation induced by trypsin and substance P remained unaffected by the preceding plasmin stimulation. The pretreatment with plasmin, thrombin, or trypsin significantly attenuated the plasmin-induced relaxation. In porcine coronary artery endothelial cells (PCAECs) and human umbilical vein endothelial cells (HUVECs), plasmin induced a transient elevation in the cytosolic Ca²⁺ concentrations ([Ca²⁺]_i). The preceding stimulation with plasmin inhibited the subsequent [Ca²⁺]_i elevation induced by thrombin but not that induced by trypsin. In PCAECs, plasmin concentration-dependently induced NO production.

Conclusions— The present study demonstrated, for the first time, that plasmin induced an endothelium-dependent NO-mediated relaxation in the porcine coronary artery, while also showing plasmin to specifically inactivate the thrombin receptor.

Plasmin is a key enzyme in fibrinolysis, although it is known to exert cellular effects. The present study demonstrated, for the first time, that plasmin induced an endothelium-dependent NO-mediated relaxation in the porcine coronary artery, while also showing plasmin to specifically inactivate the thrombin receptor.

Key Words: plasmin • proteinase-activated receptor • vasorelaxation • nitric oxide • endothelium