Role of Sphingolipids in Cardiac Ischemia

Sabbadini, Roger

Abstract

Acute cardiac ischemia such as myocardial infarction (MI) is one of the leading causes of death in the US. To date, there are no FDA-approved drugs that reduce the size of the infarct or prevent the progression to MI by directly interfering with the cell death process. Most treatments involve either medical (e.g., TPA) or procedural (e.g., angioplasty) treatments intended to reperfuse the ischemic myocardium. Evidence suggets that a very early event in the cell death process involves activation of sphingolipid signaling molecules that are largely damaging to cardiac cells. It is the goal of the proposed work in both Phase I and Phase II of this SBIR is to prove the principle that the neutral form of sphingomyelinase (nSMase) and its adaptor protein, FAN (factor associated with neutral SMase activation), are valid targets for cardioprotective therapy in patients with myocardial ischemia.These signaling components are up-stream of the MAP kinases, caspases and proto-onogenes of the death process. In addition to validating the targets, we intend to elucidate the mechanisms of action of key sphingolipid signaling molecules in producing the negative inotropy and cell death associated with acute cardiac ischemia. In Phase I of the work, we intend to surgically produce reversible cardiac infarcts in FAN and nSMase knockout mice lacking these important components of the sphingolipid signaling system. In this model of ischemia/reperfusion (IR) injury, infarct sizes as a percentage of areas of risk are expected to be reduced if the FAN/nSMase signaling system is non-functional in the KO mouse compared to control litermates. These methods will be used in conjunction with our cardiomyocyte cell culture model of IR injury provide additional proof-of-principle that the FAN/SMase signaling system is key causal factor in acute cardiac ischemia ? ?