title: 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.
  
  
  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(-/-) 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.
authors.affiliation: The Scripps Research Institute, Department of Immunology, 10550 N Torrey Pines Rd, La Jolla, CA 92037, USA.
authors.forename: Rafal
authors.initials: R
authors.lastname: Pawlinski
authors.forename: Michael
authors.initials: M
authors.lastname: Tencati
authors.forename: Craig R
authors.initials: CR
authors.lastname: Hampton
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Shishido
authors.forename: Tara A
authors.initials: TA
authors.lastname: Bullard
authors.forename: Liam M
authors.initials: LM
authors.lastname: Casey
authors.forename: Patricia
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: Matthias
authors.initials: M
authors.lastname: Kotzsch
authors.forename: Denise
authors.initials: D
authors.lastname: Spring
authors.forename: Thomas
authors.initials: T
authors.lastname: Luther
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Abe
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Pohlman
authors.forename: Edward D
authors.initials: ED
authors.lastname: Verrier
authors.forename: Burns C
authors.initials: BC
authors.lastname: Blaxall
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000503:physiopathology*; D002311:Cardiomyopathy, Dilated / Q000000981:diagnostic imaging / Q000503:physiopathology; D004452:Echocardiography; D015870:Gene Expression; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000502:physiology; D010641:Phenotype; D044463:Receptor, PAR-1 / Q000235:genetics* / Q000378:metabolism*; D015427:Reperfusion Injury / Q000503:physiopathology; D013925:Thromboplastin / Q000235:genetics; D024723:Ventricular Myosins / Q000235:genetics; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D044463:Receptor, PAR-1; D013925:Thromboplastin; D024723:Ventricular Myosins