Antoniak Silvio, Cardenas Jessica C, Buczek Laura J, Church Frank C, Mackman Nigel, Pawlinski Rafal
UNC McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Cardiology. 2017;136(4):258-268. doi: 10.1159/000452269. Epub 2016 Nov 24.
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.
血管紧张素II（Ang II）在心血管疾病中起重要作用。它还会导致凝血激活。凝血蛋白酶凝血酶通过激活蛋白酶激活受体1（PAR-1）诱导细胞反应。我们研究了PAR-1是否参与Ang II诱导的心血管重塑和炎症。
给PAR-1+/+（野生型；WT）和PAR-1-/-小鼠输注Ang II（600 ng/kg/分钟），持续长达4周。在WT小鼠中，此剂量的Ang II不会导致血压显著升高，但会引起主动脉和心脏的病理变化。输注Ang II导致主动脉血管重塑，表现为中膜壁增厚和血管周围纤维化显著增加。重要的是，PAR-1缺乏可显著减轻这两个参数。此外，与WT小鼠相比，Ang II处理的PAR-1-/-小鼠冠状动脉周围的血管周围纤维化减少。此外，与WT小鼠相比，PAR-1缺乏显著减轻了Ang II诱导的主动脉中炎性细胞因子和促纤维化基因的表达。最后，PAR-1缺乏对Ang II诱导的心脏肥大没有影响。然而，通过缩短分数测量的心脏功能在PAR-1-/-小鼠中的受损程度低于WT小鼠。
我们的数据表明，PAR-1在由Ang II的非血压依赖性作用介导的心血管重塑中起重要作用。
