Myocardial infarction induced by ischemia/reperfusion (I/R) injury is a major clinical problem. During I/R injury, damage to the endothelial barrier allows a leakage of coagulation factors into the myocardium. Tissue factor (TF), the primary activator of the coagulation cascade, is constitutively expressed in the heart. Activation of coagulation cascade by TF has been shown to play a role in myocardial infarction after I/R injury. However, the role TF:FVIIa signaling has not been investigated. The TF:FVIIa complex can activate cells by cleavage of protease activated receptor-2 (PAR-2). Both TF and PAR-2 are expressed on cardiomyocytes as well as neutrophils, which infiltrate into the myocardium after I/R injury. My preliminary data demonstrate that PAR-2 deficiency results in significant reduction of infarct size, heart remodeling and heart dysfunction after I/R injury. In this proposal I hypothesize that TF:FVIIa- dependent activation of PAR-2 on both neutrophils and cardiomyocytes contributes to myocardial infarction and heart remodeling. The proposal has two specific aims.
In Specific Aim 1 I will investigate the role of TF:FVIIa-dependent activation of PAR-2 in infarct size using an in vivo mouse model of short-term I/R injury.
In Specific Aim 2 I will determine how TF:FVIIa-PAR-2 pathway contributes to heart remodeling after long- term I/R injury. In my proposal I will use unique set of tools that allow me to distinguish between signaling and coagulation properties of TF:FVIIa complex. Understanding the role of TF:FVIIa-dependent activation of PAR-2 in injured heart may lead to the development of new therapies to reduce myocardial infarction and heart failure.
A heart attack, also called myocardial infarction, results in heart muscle damage and with time may lead to the heart failure. Reducing the size of the initial infarct decreases the chance of developing heart failure. Our data indicates that deficiency of protease activated receptor-2 (PAR-2) reduces initial infarct size, attenuates heart remodeling and improves heart function in mouse models of cardiac ischemia/reperfusion injury. Therefore, blocking PAR-2-dependent signaling may be a new strategy to prevent heart muscle damage after a heart attack and consequently reducing the chance of developing heart failure.
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