title: Protease-Activated Receptor 1 Contributes to Angiotensin II-Induced Cardiovascular Remodeling and Inflammation.
abstract: Angiotensin II (Ang II) plays an important role in cardiovascular disease. It also leads to the activation of coagulation. The coagulation protease thrombin induces cellular responses by activating protease-activated receptor 1 (PAR-1). We investigated whether PAR-1 contributes to Ang II-induced cardiovascular remodeling and inflammation.
  
  
  
  PAR-1+/+ (wild-type; WT) and PAR-1-/- mice were infused with Ang II (600 ng/kg/min) for up to 4 weeks. In WT mice, this dose of Ang II did not cause a significant increase in blood pressure but it did cause pathological changes in both the aorta and the heart. Ang II infusion resulted in vascular remodeling of the aorta, demonstrated by a significant increase in medial wall thickening and perivascular fibrosis. Importantly, both parameters were significantly attenuated by PAR-1 deficiency. Furthermore, perivascular fibrosis around coronary vessels was reduced in Ang II-treated PAR-1-/- mice compared to WT mice. In addition, PAR-1 deficiency significantly attenuated Ang II induction of inflammatory cytokines and profibrotic genes in the aortas compared to WT mice. Finally, PAR-1 deficiency had no effect on Ang II-induced heart hypertrophy. However, the heart function measured by fractional shortening was less impaired in PAR-1-/- mice than in WT mice.
  
  
  
  Our data indicate that PAR-1 plays a significant role in cardiovascular remodeling mediated by a blood pressure-independent action of Ang II.
authors.affiliation: UNC McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Silvio
authors.initials: S
authors.lastname: Antoniak
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Cardenas
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Buczek
authors.forename: Frank C
authors.initials: FC
authors.lastname: Church
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
authors.forename: Rafal
authors.initials: R
authors.lastname: Pawlinski
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage*; D000818:Animals; D001011:Aorta / Q000473:pathology*; D001794:Blood Pressure; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D003331:Coronary Vessels / Q000473:pathology; D005355:Fibrosis; D006973:Hypertension / Q000139:chemically induced; D007249:Inflammation / Q000139:chemically induced; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D044463:Receptor, PAR-1 / Q000235:genetics*; D015398:Signal Transduction; D066253:Vascular Remodeling / Q000235:genetics*
chemical_list: D044463:Receptor, PAR-1; D000804:Angiotensin II