Protease-Activated Receptor 1 Contributes to Angiotensin II-Induced Cardiovascular Remodeling and Inflammation

Background: 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 inflamma- tion. Methods and Results: 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 path- ological changes in both the aorta and the heart. Ang II infu- sion resulted in vascular remodeling of the aorta, demon- strated 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 addi- tion, PAR-1 deficiency significantly attenuated Ang II induc- tion 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. Conclusion: Our data indicate that PAR-1 plays a significant role in cardiovas- cular remodeling mediated by a blood pressure-indepen- dent action of Ang II.