Protein activated Receptor-4 in Cardiac Rupture after Myocardial Infarction

心脏破裂是急性心肌梗死（MI）的主要致死性并发症。尽管取得了重大进展 在再灌注策略中，心脏破裂的死亡率仍然很高。临床和实验研究 已经提供了强有力的证据表明，心肌梗死早期的室壁破裂主要是过度 肌细胞损失和局部炎症。以缺血心肌再灌注为目标的溶栓治疗 显示出相互矛盾的结果，因为它们似乎增加了动脉瘤形成和破裂的风险。分子 溶栓治疗影响心脏重塑和破裂的机制仍然是未知的。 最近的证据表明，溶栓丝氨酸蛋白酶的生理功能超出了 在调节炎症和对组织损伤的修复反应中起关键作用 蛋白酶激活受体（PARs）。PAR1是心肌细胞中凝血酶作用的主要受体 和血小板。然而，使用PAR1抑制剂抑制重塑与严重出血有关， 这限制了它们的临床应用。我们最近报道了一种额外的凝血酶受体PAR 4的表达， 心脏被高浓度的凝血酶激活，使PAR4成为一个潜在的治疗靶点， 与高凝血酶浓度相关的情况，如MI。然而，对PAR4功能知之甚少 在心脏。我们在PAR 4缺陷小鼠中的初步数据显示，在MI后2天， 死亡，减少梗死面积和改善功能恢复相对于野生型（WT）。然而，在更长的时间里， 心肌梗死后，PAR4缺陷小鼠表现出心脏功能受损，炎性细胞浸润延迟， 心肌破裂率高于WT。随后的研究，以描绘涉及的机制 支持PAR4信号传导在中性粒细胞凋亡中的作用，其在炎症消退中起重要作用。 这些研究表明，心肌细胞中PAR4信号的丢失可能具有心脏保护作用，解释了心肌细胞中PAR4信号的早期缺失。 但是炎性细胞中PAR4的缺失会破坏MI后伤口愈合，并可能导致心脏病。 功能障碍和壁破裂。我们将在目标1中研究在心肌细胞中PAR4信号转导的激活是否在心肌细胞中。 MI促进心肌细胞死亡和心功能障碍。在目标2中，我们将确定PAR4信号传导的激活是否 中性粒细胞在MI后促进其死亡后浸润到受损心脏产生正常伤口 治愈最后，目的3将研究PAR4介导的中性粒细胞凋亡对炎症的影响。 MI后的消退和心脏愈合。拟议的实验将确定新的细胞靶点， 溶栓丝氨酸蛋白酶和PAR 4影响MI后心肌愈合， 血液凝固，并将测试是否靶向心肌细胞或炎症细胞中的PAR4将提供新的 降低MI后死亡率的策略，包括心室破裂引起的死亡率。

Cardiac rupture is a major lethal complication of acute myocardial infarction (MI). Despite significant advances in reperfusion strategies, mortality from cardiac rupture remains high. Both clinical and experimental studies have provided strong evidence that wall rupture at an early stage of MI is mainly the consequence of excessive myocyte loss and regional inflammation. Thrombolytic therapy aiming to reperfuse the ischemic myocardium showed conflicting results as they seem to increase the risk of aneurysm formation and rupture. The molecular mechanisms by which thrombolytic therapy affects cardiac remodeling and rupture are still largely unknown. Recent evidence has shown that the physiological functions of thrombolytic serine proteases extend beyond blood coagulation and play a pivotal role in modulating inflammatory and repair responses to tissue injury in part via protease-activated receptors (PARs). PAR1 is the predominant receptor for thrombin actions in cardiac cells and platelets. However, the use of PAR1 inhibitors to suppress remodeling was associated with severe bleeding, which limit their clinical use. We recently reported the expression of an additional thrombin receptor, PAR4, in the heart that is activated by high concentrations of thrombin, making PAR4 a potential therapeutic target in situations associated with high thrombin concentrations such as MI. However, little is known about PAR4 function in the heart. Our preliminary data in PAR4-deficient mice show that at 2 days after MI there is decreased myocyte death, reduced infarct size and improved functional recovery relative to wild-type (WT). However, at longer times after MI, PAR4-deficient mice showed impaired cardiac function, delayed infiltration of inflammatory cells, and greater rates of myocardial rupture relative to WT. Subsequent studies to delineate the mechanisms involved support a role of PAR4 signaling in neutrophil apoptosis, which plays an important role in inflammation resolution. These studies suggest that loss of PAR4 signaling in myocytes might be cardioprotective, explaining the early effects, but loss of PAR4 in inflammatory cells disrupts post-MI wound healing and can lead to cardiac dysfunction and wall rupture. We will investigate in aim 1 if activation of PAR4 signaling in cardiomyocytes after MI promotes myocyte death and cardiac dysfunction. In aim 2, we will determine if activation of PAR4 signaling in neutrophils after MI promotes their death after infiltration into the damaged heart to produce normal wound healing. Finally, aim 3 will investigate the impact of PAR4-mediated neutrophil apoptosis on inflammation resolution and cardiac healing post-MI. The proposed experiments will identify novel cell targets by which thrombolytic serine proteases and PAR4 influence myocardial healing post-MI independently of their effects on blood coagulation and will test whether targeting PAR4 in cardiomyocytes or inflammatory cells would offer novel strategies to reduce the incidence of mortality after MI, including mortality caused by ventricular rupture.