A heart attack occurs when a blood clot forms in a coronary artery depriving blood flow from a region of the heart, a condition termed ischemia. Current therapy is to reopen the artery but blood flow is seldom restored before a significant amount of the heart muscle has died. Because lost heart muscle cannot be regenerated the patient is left with a weakened heart and heart failure often occurs. Our research is directed toward identifying therapies that prevent cell death in ischemic heart. We have found that population of Gi-coupled receptors prior to ischemia makes the heart very resistant to cell death. Our current research is directed at mapping the complex signal transduction pathway involved. To date we have found that population of surface receptors with bradykinin or opioids, through their G-proteins, cause transactivation of epidermal growth factor receptors. That in turn activates PI3 kinase which causes activation of Akt through phosphorylation. Akt activation results ultimately in opening of mitochondrial ATP sensitive potassium channels, mKATP. As potassium enters the mitochondria it causes them to release free radicals which act as a signal to activate protective kinases such as PKC.
We study this pathway using whole hearts where we measure tissue death after a standardized ischemic insult as an end-point. We can then use pharmacologic tools to both trigger and block the protection at specific points in the pathway. Secondly, we study heart samples from hearts receiving various treatments and measure the chemical signals directly using protein chemistry. Finally, we study isolated heart muscle cells where the free radical burst can be measured with radical-sensitive dyes and again use activators and blockers to determine the steps between the receptor activation and the free radical burst
Our research is directed toward identifying therapies that prevent cell death in ischemic heart.
