Protease-activated receptor 4 deficiency offers cardioprotection after acute ischemia reperfusion injury.
Protease-activated receptor 4 deficiency offers cardioprotection after acute ischemia reperfusion injury.
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DOI：
10.1016/j.yjmcc.2015.11.030
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发表时间：
2016-01
影响因子：
5
通讯作者：
Sabri A
中科院分区：
文献类型：
--
作者：
Kolpakov MA;Rafiq K;Guo X;Hooshdaran B;Wang T;Vlasenko L;Bashkirova YV;Zhang X;Chen X;Iftikhar S;Libonati JR;Kunapuli SP;Sabri A
蛋白酶激活受体（PAR）4是一种低亲和力凝血酶受体，相对于PAR 1，其功能了解较少。PAR4参与血小板活化和止血，但其对肌细胞生长和心脏功能的具体作用尚不清楚。本研究探讨PAR4缺陷对小鼠心肌缺血再灌注损伤的保护作用。当受到体内或离体IR攻击时，PAR4敲除（KO）小鼠表现出对损伤的耐受性增加，这表现为与野生型小鼠相比梗死面积减小和功能恢复更稳健。PAR4基因敲除小鼠还表现出减少心肌细胞凋亡和假定的信号转移的生存途径在IR。PAR4表达的抑制在分离的心肌细胞的shRNA提供保护，对凝血酶和PAR4激动剂肽诱导的细胞凋亡，而野生型PAR4的过度表达显着增强心肌细胞凋亡的易感性，即使在低凝血酶浓度。进一步的研究暗示Src和表皮生长因子受体依赖性激活JNK对PAR4在心肌细胞中的促凋亡作用。这些发现揭示了PAR 4作为心肌细胞存活的调节剂的关键作用，并指出PAR 4抑制作为急性IR损伤后提供心脏保护的治疗靶点。
Protease-activated receptor (PAR)4 is a low affinity thrombin receptor with less understood function relative to PAR1. PAR4 is involved in platelet activation and hemostasis, but its specific actions on myocyte growth and cardiac function remain unknown. This study examined the role of PAR4 deficiency on cardioprotection after myocardial ischemia-reperfusion (IR) injury in mice. When challenged by in vivo or ex vivo IR, PAR4 knockout (KO) mice exhibited increased tolerance to injury, which was manifest as reduced infarct size and a more robust functional recovery compared to wild-type mice. PAR4 KO mice also showed reduced cardiomyocyte apoptosis and putative signaling shifts in survival pathways in response to IR. Inhibition of PAR4 expression in isolated cardiomyocytes by shRNA offered protection against thrombin and PAR4-agonist peptide-induced apoptosis, while overexpression of wild-type PAR4 significantly enhanced the susceptibility of cardiomyocytes to apoptosis, even under low thrombin concentrations. Further studies implicate Src- and epidermal growth factor receptor-dependent activation of JNK on the proapoptotic effect of PAR4 in cardiomyocytes. These findings reveal a pivotal role for PAR4 as a regulator of cardiomyocyte survival and point to PAR4 inhibition as a therapeutic target offering cardioprotection after acute IR injury.