Abstract
Proteaseβactivated receptors (PARs) are widely expressed within the heart. They are activated by a myriad of proteases, including coagulation proteases. In vitro studies showed that activation of PARβ1 and PARβ2 on cardiomyocytes induced hypertrophy. In addition, PARβ1 stimulation on cardiac fibroblasts induced proliferation. Genetic and pharmacologic approaches have been used to investigate the role of the different PARs in cardiac ischemia/reperfusion (I/R) injury. In mice and rats, PARβ1 is reported to play a role in inflammation, infarct size, and remodeling after cardiac I/R injury. However, there are notable differences between the effect of a deficiency in PARβ1 and inhibition of PARβ1. For instance, inhibition of PARβ1 reduced infarct size whereas there was no effect of a deficiency of PARβ1. These differences maybe due to offβtarget effects of the inhibitor or PARβ4 compensation of PARβ1 deficiency. Similarly, a deficiency of PARβ2 was associated with reduced cardiac inflammation and improved heart function after I/R injury, whereas pharmacologic activation of PARβ2 was found to be protective due to increased vasodilatation. These differences maybe due to different signaling responses induced by an endogenous protease versus an exogenous agonist peptide. Surprisingly, PARβ4 deficiency resulted in increased cardiac injury and increased mortality after I/R injury. In contrast, a pharmacological study indicated that inhibition of PARβ4 was cardioprotective. It is possible that the major cellular target of the PARβ4 inhibitor is platelets, which have been shown to contribute to inflammation in the injured heart, whereas PARβ4 signaling in cardiomyocytes may be protective. These discrepant results between genetic and pharmacological approaches indicate that further studies are needed to determine the role of different PARs in the injured heart. Β© 2011 IUBMB IUBMB Life, 63(6): 383β389, 2011