Protein activated Receptor-4 in Cardiac Rupture after Myocardial Infarction

心脏破裂是急性心肌梗死(MI)的主要致命性并发症。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 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的后果 心肌细胞丢失和局部炎症。以缺血心肌再灌流为目标的溶栓治疗 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构和破裂的机制目前仍不清楚。 最近的证据表明，溶栓丝氨酸蛋白酶的生理功能超出了 凝血蛋白在组织损伤的炎症和修复反应中起着关键作用 通过蛋白水解酶激活受体(PARs)。PAR1是心肌细胞中凝血酶作用的主要受体 还有血小板。然而，使用PAR1抑制剂抑制重构与严重出血有关， 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PAR4的表达。 由高浓度凝血酶激活的心脏，使PAR4成为潜在的治疗靶点 与高凝血酶浓度相关的情况，如心肌梗塞。然而，人们对PAR4功能知之甚少 在内心深处。我们对PAR4缺陷小鼠的初步数据显示，在心肌梗死后2天，心肌细胞减少 与野生型(WT)相比，死亡、缩小梗死范围和改善功能恢复。然而，在更长的时间里， 心肌梗死后，PAR4缺陷小鼠表现出心功能受损，炎性细胞浸润延迟，以及 与WT相比，心肌破裂的发生率更高。随后的研究以描述所涉及的机制 支持PAR4信号在中性粒细胞凋亡中的作用，这在炎症消退中起着重要作用。 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，这解释了早期的 但炎性细胞中PAR4的缺失扰乱了MI后伤口的愈合，并可导致心脏 功能障碍和室壁破裂。我们将在目标1中研究心肌细胞中PAR4信号的激活是否在 心肌梗死促进心肌细胞死亡和心功能不全。在目标2中，我们将确定PAR4信号的激活 在中性粒细胞心肌梗塞后促进其死亡后渗入受损的心脏以产生正常伤口 治愈。最后，Aim 3将研究PAR4介导的中性粒细胞凋亡对炎症的影响 心肌梗死后的分辨率和心脏愈合。拟议的实验将识别新的细胞靶标，通过 溶栓性丝氨酸蛋白酶和PAR4对心肌梗死后心肌愈合的影响不依赖于它们对 并将测试靶向心肌细胞或炎症细胞中的PAR4是否会提供新的 减少心肌梗死后死亡率的策略，包括由脑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.