James M. Downey, Ph.D.

Professor

Research Interests:

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, mK_ATP. 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. Drugs that activate this pathway can protect the heart when they are given at reperfusion and are therefore clinically very relevant.

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 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.

 

Recent Publications:

• Cohen MV, Yang XM, Downey JM. The pH hypothesis of postconditioning: staccato reperfusion reintroduces oxygen and perpetuates myocardial acidosis. Circulation.115:1895-903.  2007
• Tissier R, Hamanaka K, Kuno A, Parker JC, Cohen MV, Downey JM. Total liquid ventilation provides ultra-fast cardioprotective cooling. 49:601-5. J Am Coll Cardiol. 2007
• Kuno A, Critz SD, Cui L, Solodushko V, Yang XM, Krahn T, Albrecht B, Philipp S, Cohen MV, Downey JM. Protein kinase C protects preconditioned rabbit hearts by increasing sensitivity of adenosine A(2b)-dependent signaling during early reperfusion. J Mol Cell Cardiol. (in press) 2007
• Kuno A, Solenkova NV, Solodushko V, Dost T, Liu Y, Yang XM, Cohen MV, Downey JM. Infarct limitation by a protein kinase G activator at reperfusion in rabbit hearts is dependent on sensitizing the heart to A2b agonists by protein kinase C. Am J Physiol Heart Circ Physiol.  295:H1288-H1295, 2008
•  Dost T, Cohen MV, Downey JM. Redox signaling triggers protection during the reperfusion rather than the ischemic phase of preconditioning. Basic Res Cardiol.  103:378-84. 2008
• Krieg T, Liu Y, Rütz T, Methner C, Yang XM, Dost T, Felix SB, Stasch JP, Cohen MV, Downey JM. BAY 58-2667, a nitric oxide-independent guanylyl cyclase activator, pharmacologically post-conditions rabbit and rat hearts. Eur Heart J.30:1607-13. 2009

•  Yang XM, Liu Y, Liu Y, Tandon N, Kambayashi J, Downey JM, Cohen MV. Attenuation of infarction in cynomolgus monkeys: preconditioning and postconditioning. Basic Res Cardiol. 2009 Aug 8.(epub ahead of print)

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

Phone: 251 460 6818
FAX: 251 460 6386

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