Department of Physiology
College of Medicine
University of South Alabama
Department of Physiology
5851 USA Dr. N., MSB 3074
University of South Alabama
Mobile, Alabama 36688
Ph.D., University of Illinois
Postdoctoral Studies: Harvard Medical School
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.
Our current interest is in the pathways that are active when the preconditioned heart is reperfused after the ischemic insult. PKC sensitizes the heart to adenosine at the A2b receptor. That allows endogenous adenosine to activate signaling from this normally low affinity receptor. The A2b receptor controls the survival kinases ERK and Akt in the heart. Those kinases are thought to act through GSK3B to inhibit the mitochondrial permeability transition pore formation that destroys many of the heart's mitochondria in the first minutes of reperfusion. Many drugs and interventions that can activate the conditioning pathway have been identified.
We study these pathways 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 involved in signaling 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. We found that platelet inhibitors belonging to the P2Y12 inhibitor family put the heart into a preconditioned state if they are present in the blood at the time of reperfusion. Since most of today's patients treated for acute myocardial infarction receive a loading dose of a P2Y12 blocker prior to reperfusion therapy they are already in a preconditioned state. That would explain why powerful preconditioning mimetics have performed poorly in recent clinical trials. What is needed is a drug that protects by a different mechanism than the conditioning pathway.
Most recently I have become interested in the role of mitochondrial DNA as a promoter of cell death during acute myocardial infarction. I proposed that fragmented mitochondrial DNA released from irreversibly injured mitochondria acts as a DAMP (damage associated molecular pattern) and triggers a local inflammatory reaction in adjacent cells which kills them causing them to release their mitoDNA. This causes a spreading wave of necrosis across the ischemic zone. IV injection of mitochondrially-directed DNA repair enzymes or of DNase prevents this domino effect and greatly limits infarct size. The executioner of the inflammation appears to be caspase-1 as we find caspase-1 inhibitors to be highly protective. Because these drugs protect by a different mechanism than conditioning they can further limit infarct size in animals already protected with a platelet inhibitor.
I have been teaching cardiovascular physiology to the freshman medical students since 1972, first at the University of South Florida and then at my present location at the University of South Alabama. I developed a number of interactive teaching laboratories to complement my lectures. Originally those laboratories involved live animals but today they either use student volunteers (ECG lab) or computer simulations including the USA cardiovascular simulator which is a free downloadable teaching program that the student can use to illustrate the complex the interaction between the heart, whos output is determined by its preload and afterload, and the peripheral vasculature that actually determines preload and afterload. In 1992 I contributed 8 cardiovascular chapters to Johnson’s Essential Medical Physiology (Raven). This was a text book designed for medical students and was adopted by a number of medical schools as an assigned text. It was revised in 1998 and again in 2003 (Elsevier). I still lecture in our cardiovascular modules for the medical students and for the graduate students.
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