Department of Physiology, University of Tennessee Health Science Center, Memphis.
Circulation. 2018 Nov 20;138(21):2395-2412. doi: 10.1161/CIRCULATIONAHA.118.034083.
Although the role of thrombin in atherothrombosis is well studied, its role in the pathogenesis of diet-induced atherosclerosis is not known.
Using a mouse model of diet-induced atherosclerosis and molecular biological approaches, here we have explored the role of thrombin and its G protein-coupled receptor signaling in diet-induced atherosclerosis.
In exploring the role of G protein-coupled receptor signaling in atherogenesis, we found that thrombin triggers foam cell formation via inducing CD36 expression, and these events require Par1-mediated Gα12-Pyk2-Gab1-protein kinase C (PKC)θ-dependent ATF2 activation. Genetic deletion of PKCθ in apolipoprotein E (ApoE) mice reduced Western diet-induced plaque formation. Furthermore, thrombin induced Pyk2, Gab1, PKCθ, and ATF2 phosphorylation, CD36 expression, and foam cell formation in peritoneal macrophages of ApoE mice. In contrast, thrombin only stimulated Pyk2 and Gab1 but not ATF2 phosphorylation or its target gene CD36 expression in the peritoneal macrophages of ApoE:PKCθ mice, and it had no effect on foam cell formation. In addition, the aortic root cross-sections of Western diet-fed ApoE mice showed increased Pyk2, Gab1, PKCθ, and ATF2 phosphorylation and CD36 expression as compared with ApoE:PKCθ mice. Furthermore, although the monocytes from peripheral blood and the aorta of Western diet-fed ApoE mice were found to contain more of Ly6C cells than Ly6C cells, the monocytes from Western diet-fed ApoE:PKCθ mice were found to contain more Ly6C cells than Ly6C cells. It is interesting to note that the Ly6C cells showed higher CD36 expression with enhanced capacity to form foam cells as compared with Ly6C cells.
These findings reveal for the first time that thrombin-mediated Par1-Gα12 signaling via targeting Pyk2-Gab1-PKCθ-ATF2-dependent CD36 expression might be playing a crucial role in diet-induced atherogenesis.
尽管已有研究深入探讨了凝血酶在动脉血栓形成中的作用，但凝血酶在饮食诱导的动脉粥样硬化发病机制中的作用尚不清楚。
利用饮食诱导动脉粥样硬化的小鼠模型和分子生物学方法，我们在此探索了凝血酶及其 G 蛋白偶联受体信号在饮食诱导的动脉粥样硬化中的作用。
在探索 G 蛋白偶联受体信号在动脉粥样发生中的作用时，我们发现凝血酶通过诱导 CD36 表达触发泡沫细胞形成，这些事件需要 Par1 介导的 Gα12-Pyk2-Gab1-PKCθ 依赖性 ATF2 激活。载脂蛋白 E (ApoE) 小鼠中 PKCθ 的基因缺失减少了西方饮食诱导的斑块形成。此外，凝血酶诱导 ApoE 小鼠腹腔巨噬细胞中的 Pyk2、Gab1、PKCθ 和 ATF2 磷酸化、CD36 表达和泡沫细胞形成。相比之下，凝血酶仅刺激 ApoE：PKCθ 小鼠的腹腔巨噬细胞中的 Pyk2 和 Gab1，但不刺激 ATF2 磷酸化或其靶基因 CD36 表达，并且对泡沫细胞形成没有影响。此外，与 ApoE：PKCθ 小鼠相比，西方饮食喂养的 ApoE 小鼠主动脉根部切片显示 Pyk2、Gab1、PKCθ 和 ATF2 磷酸化和 CD36 表达增加。此外，尽管外周血中的单核细胞和西方饮食喂养的 ApoE 小鼠的主动脉中发现 Ly6C 细胞比 Ly6C 细胞含有更多的 Ly6C 细胞，但西方饮食喂养的 ApoE：PKCθ 小鼠中的单核细胞含有更多的 Ly6C 细胞。有趣的是，与 Ly6C 细胞相比，Ly6C 细胞表现出更高的 CD36 表达和形成泡沫细胞的能力增强。
这些发现首次揭示，凝血酶通过靶向 Pyk2-Gab1-PKCθ-ATF2 依赖性 CD36 表达的 Par1-Gα12 信号传导，可能在饮食诱导的动脉粥样发生中发挥关键作用。
