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(Circulation Research. 2002;90:366.)
© 2002 American Heart Association, Inc.

Editorials

PAR2 Is Partout and Now in the Heart

Andrew Maree, Desmond Fitzgerald

From the Institute of Biopharmaceutical Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.

Correspondence to Desmond Fitzgerald, MD, Royal College of Surgeons in Ireland, St Stephens Green, Dublin 2, Ireland. E-mail dfitzgerald@rcsi.ie

Key Words: protease-activated receptor • myocardial ischemia • reperfusion injury • thrombin • trypsin

Endothelial cell injury is a common accompaniment of cardiovascular disease, often evident as an attenuation of endothelial-dependent vasorelaxation. Vascular generation of nitric oxide (NO) in response to a variety of agonists is impaired in diabetes, atherosclerosis, and even isolated hyperlipidemia. Altered NO production may contribute not only to abnormal vascular resistance but also to the development of smooth muscle cell proliferation within the vessel. An acute endothelial injury is sustained during reperfusion of ischemic myocardium. Free radical generation results in endothelial dysfunction, limiting coronary flow in the reperfused segment and further hindering myocardial function. Cardioprotective effects of NO are inhibited; indeed, its interaction with superoxide may well be cytotoxic.¹ However, in this issue of Circulation Research, McLean and colleagues² demonstrate that endothelial dysfunction resulting from reperfusion injury is selective. One novel pathway, protease-activated receptor (PAR)-mediated coronary vasodilation, remains intact, making it a potential therapeutic target to maintain coronary blood flow.

PARs are cell surface membrane receptors activated by the serine proteases thrombin and trypsin. Thus, thrombin and trypsin, in addition to their well-characterized proteolytic activity, play an integral role in cell signaling.³ PARs are G protein-coupled transmembrane receptors with 7 helical hydrophobic domains that criss-cross the cell membrane. They possess a C-terminal intracellular tail and a long N-terminal extracellular domain. To date, 4 such receptors (PAR1, -2, -3, and -4) have been identified, each displaying a similar mechanism of protease dependent activation.

PAR1 is an important receptor for thrombin-mediated platelet activation, although PAR3 and PAR4 are also involved.⁴ PAR1 . . . [Full Text of this Article]