Protease-Activated Receptor 1 Contributes to Angiotensin II-Induced Cardiovascular Remodeling and Inflammation.
Protease-Activated Receptor 1 Contributes to Angiotensin II-Induced Cardiovascular Remodeling and Inflammation.
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DOI：
10.1159/000452269
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发表时间：
2017
期刊：
影响因子：
1.9
通讯作者：
Pawlinski R
中科院分区：
文献类型：
--
作者：
Antoniak S;Cardenas JC;Buczek LJ;Church FC;Mackman N;Pawlinski R
血管紧张素II(Ang II)在心血管疾病中起重要作用。它还会导致凝血的激活。凝血酶凝血酶通过激活蛋白酶激活受体1(PAR-1)来诱导细胞反应。我们研究了PAR-1是否参与血管紧张素转换酶II诱导的心血管重构和炎症。给PAR-1+/+(WT)和PAR-1−/−小鼠静脉注射血管紧张素Ⅱ(600 ng/kg/min)，连续4周。在WT小鼠中，此剂量的Ang II并未导致血压显著升高，但导致了主动脉和心脏的病理变化。血管紧张素转换酶II可导致血管重塑，表现为血管内壁增厚和血管周围纤维化明显增加。重要的是，这两个参数都因PAR-1缺乏而显著减弱。此外，与WT小鼠相比，经血管紧张素转换酶II治疗的PAR-1−/−小鼠冠状动脉周围血管周围纤维化减轻。此外，与WT小鼠相比，PAR-1缺乏显著减弱了Ang II对大动脉炎症细胞因子和促纤维化基因的诱导。PAR-1缺乏对Ang II诱导的心肌肥厚无影响。然而，通过缩短分数测量的心功能，在PAR-1−/−组比在WT小鼠中受到的损害更小。我们的数据表明，PAR-1在血管紧张素转换酶II的血压非依赖性作用所介导的心血管重塑中起重要作用。
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 if PAR-1 contributes to Ang II-induced cardiovascular remodeling and inflammation. PAR-1+/+ (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 the blood pressure but caused pathological changes in both the aorta and 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 the 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−/− than in WT mice. Our data indicated that PAR-1 plays a significant role in cardiovascular remodeling mediated by a blood pressure-independent action of Ang II.