Abstract 12292: GsMTx4-D is a Cardioprotectant Against Myocardial Infarction During Ischemia and Reperfusion

Abstract

Introduction: Reperfusion of ischemic cardiac tissue by percutaneous coronary intervention has become a routine treatment for acute ST-elevation myocardial infarction. However, restoring blood flow to ischemic cardiac tissue can injure myocytes that were viable prior to reperfusion. The putative causes of ischemia/reperfusion (I/R) injury are varied, though cation imbalance has long been known to be a significant contributor. GsMTx4 peptide is a selective inhibitor of cation selective mechanosensitive ion channels (MSCs) and has helped establish the role of MSCs in cardiac physiology. However, the role of MSCs in ischemic reperfusion injury remain uncertain. Hypothesis: Pathological stresses from swelling and hypercontracture during I/R can activate cationic MSCs, the D enantiomer of GsMTx4 can act as a cardioprotectant during I/R. Methods: GsMTx4-D pharmacokinetics in the plasma and heart was monitored over 24 h using an LCMSMS assay. The cardioprotective activities of GsMTx4 were monitored in a mouse model of ischemia/reperfusion (I/R) injury in which the left anterior descending coronary artery (LAD) was occluded and then released. The influence of GsMTx4 on contractile function and transient calcium signaling of cardiomyocyte were assessed by SoftEdge MyoCam system. Results: GsMTx4-D reduced infarct area by >40% for both acute and pretreated animals relative to vehicle injected animals (p<0.01). Cardiac output was significantly improved in GsMTx4-D pretreatment group, and arrhythmias were also significantly reduced by intravenous injections of GsMTx4-D. The further studies with isolated cardiomyocytes revealed that GsMTx4-D improved contractility and intracellular transient calcium signaling of cardiomyocytes under hypoxia/reoxygenation conditions. The immunoblotting data demonstrated that administration of GsMTx4-D attenuated I/R-induced inflammatory c-Jun N-terminal protein kinase (JNK) and NF-κB signaling pathways in the hearts. Conclusions: GsMTx4-D is a potent cardioprotectant that decreases infarct area, improves heart function, reduces arrhythmias and attenuates inflammatory signaling pathways that are caused by I/R. Thus GsMTx4-D could be a useful therapy in treating cardiac I/R injury.