Professor
Department of Physiology,
University of South Alabama
College of Medicine
MSB 3074
Mobile, AL 36688
E-mail: mcohen@southalabama.edu

Mailing address: Department of Physiology
Room 3074 Medical Science Building
University of South Alabama
College of Medicine
Mobile, Alabama 36688

Phone: 251-460-6812
FAX: 251-460-6464

M.D., Harvard Medical School
Cardiology Fellowship: Peter Bent Brigham Hospital, Boston, MA

Research Interests:

When a coronary artery is obstructed by either cholesterol plaque or thrombus, the region served by that artery loses its blood supply and, therefore, its supply of oxygen and metabolite. Heart muscle cells begin to die within 15 or 20 minutes. To restore coronary flow in these patients thrombolytic drugs can be given to dissolve the blood clot or catheter-based techniques can be used to remove or compress the plaque and reestablish luminal patency. Unfortunately there is always some delay in restoration of flow, and there is always unavoidable death of heart muscle. Because heart muscle cells cannot be regenerated, the loss of contractile mass leaves the patient with a permanently weakened heart which often leads to heart failure, a major cause of morbidity and death in these patients. The goal of my research is discovery of an intervention which will delay the rate of cell death in such a patient so that more muscle would survive the heart attack.


In 1986, it was shown that heart cells could be made very resistant to death following loss of blood flow if they were first exposed to a brief period of blood flow deprivation followed by reperfusion. Within minutes of this cycle of ischemia/reperfusion the heart actually adapted itself to much better tolerate a subsequent, more prolonged cessation of blood flow. If understood, this process, called preconditioning, should provide a key to designing a therapy which could spare ischemic myocardium. My colleague James M. Downey and I have studied the signaling involved in preconditioning and have identified many of the critical steps including binding of Gi-coupled adenosine, bradykinin, and opioid receptors, downstream activation of Akt, ERK, and nitric oxide synthase, opening of KATP channels and release of reactive oxygen species, and activation of PKC which somehow sensitizes adenosine A2B receptors allowing successful ligand binding. This in turn leads to phosphorylation of other kinases including ERK, Akt, nitric oxide synthase, and GSK-3β with the ultimate goal of closing mitochondrial permeability transition pores, the putative end-effectors. However, the intellectual satisfaction at uncovering this signaling is challenged by the poor likelihood that there would ever be a derived intervention that could be clinically useful since this preconditioning must be initiated before ischemia, whereas patients present with myocardial infarction following coronary occlusion and onset of ischemia.


But then it became apparent that brief coronary occlusions immediately after a cycle of ischemia/reperfusion were just as effective as preconditioning in which the brief occlusions occurred before the long coronary occlusion. Thus postconditioning could effectively decrease infarction. And this phenomenon could be replicated with certain pharmacologic agents administered just before reperfusion. One family of agents we have extensively studied is platelet anti-aggregatory P2Y12 receptor antagonists such as cangrelor and ticagrelor. And now virtually all patients with acute myocardial infarction receive these agents before catheter-based interventions to remove thrombus and restore perfuson. Hence all of these patients are indeed postconditioned and “protected”. Despite use of these cardioprotective drugs, infarction is not eliminated. We are now identifying interventions which can be used to augment protection induced by P2Y12 agents. Although hypothermia and cariporide can each augment cardioprotection, neither can easily be used clinically. But a caspase-1 antagonist which blunts inflammation and pyroptosis has proven to be quite promising. Future research will seek to establish the mechanism and properties to permit extrapolation to clinical use.

Recent Publications:

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