Protease-Activated Receptor-1 Contributes to Cardiac Remodeling and Hypertrophy

Abstract

Background-Protease-activated receptor-1 (PAR-1) is the high-affinity receptor for the coagulation protease thrombin. It is expressed by a variety of cell types in the heart, including cardiomyocytes and cardiac fibroblasts. We have shown that tissue factor (TF) and thrombin contribute to infarct size after cardiac ischemia-reperfusion (I/R) injury. Moreover, in vitro studies have shown that PAR-1 signaling induces hypertrophy of cardiomyocytes and proliferation of cardiac fibroblasts. The purpose of the present study was to investigate the role of PAR-1 in infarction, cardiac remodeling, and hypertrophy after I/R injury. In addition, we analyzed the effect of overexpression of PAR-1 on cardiomyocytes. Methods and Results-We found that PAR-1 deficiency reduced dilation of the left ventricle and reduced impairment of left ventricular function 2 weeks after I/R injury. Activation of ERK1/2 was increased in injured PAR-1 Ϫ/Ϫ mice compared with wild-type mice; however, PAR-1 deficiency did not affect infarct size. Cardiomyocyte-specific overexpression of PAR-1 in mice induced eccentric hypertrophy (increased left ventricular dimension and normal left ventricular wall thickness) and dilated cardiomyopathy. Deletion of the TF gene in cardiomyocytes reduced the eccentric hypertrophy in mice overexpressing PAR-1.Conclusions-Our results demonstrate that PAR-1 contributes to cardiac remodeling and hypertrophy. Moreover, overexpression of PAR-1 on cardiomyocytes induced eccentric hypertrophy. Inhibition of PAR-1 after myocardial infarction may represent a novel therapy to reduce hypertrophy and heart failure in humans.

Adipose-derived regenerative cells exert beneficial effects on systemic responses following myocardial ischemia/reperfusion

“…Inhibition of factor Xa has been shown to reduce inflammation in a model of acute myocardial I/R injury [21]. This protective effect has been associated with phosphorylation of ERK1/2 and STAT-3 [22,23]. These results support the hypothesis that reduction of factor Xa expression in the liver may be one of the cardiprotective effects caused by ADRC administration.…”

PAR1 contributes to influenza A virus pathogenicity in mice

“…Accordingly, the natural PAR1 activator thrombin was generated in IAV-infected lungs (45), and elevated levels of PAR1 were observed in the airways of IAV-infected mice (17). It is worth noting, however, that SCH79797 is known to have off-target effects on cell proliferation and survival (46,47); thus, we cannot exclude PAR1-independent effect of SCH79797. However, SCH79797 was capable of inhibiting PAR1 signaling ( Figure 4A and ref.…”

Involvement of Protein Kinase C and RhoA in Protease-Activated Receptor 1–Mediated F-Actin Reorganization and Cell Growth in Rat Cardiomyocytes

“…There is now substantial evidence that PAR1 stimulation modulates several cardiac cell functions, for example, an increase in contractility and the occurrence of arrhythmia (8,9). Furthermore, hypertrophic cell growth has been observed in rat neonatal cardiac myocytes after long-term treatment with thrombin (5,10,11) and in mouse heart overexpressing PAR1 (12). However, the molecular mechanism by which PAR1 leads to these functional and morphological changes, especially hypertrophic cell growth, has not been identified.…”