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Assistant Professor Department of Physiology

Email: brownda@ecu.edu

Mailing Address:
Brody School of Medicine
Department of Physiology
600 Moye Blvd.
Greenville, NC 27834

What causes cardiac arrhythmias? Why do heart cells die if they are deprived of oxygen? What can we do to decrease ischemia/reperfusion injury in the heart? My laboratory is interested in these broad questions.

Ischemic Heart Disease claims more human lives each year than any other single disease. The most common manifestations of ischemic heart disease are arrhythmia and myocardial infarction, yet the mechanisms underlying these phenomena have yet to be fully elucidated. Investigating these mechanisms and understanding how they are altered between health and disease is a goal of our research.

My laboratory focuses on cardiac electrophysiology, spanning the level of the intact heart down to isolated heart cells (myocytes) and further down to the powerhouses of the cell (mitochondria). A major question that we are interested in investigating is: How does the metabolic state of the heart influence the activity of cardiac ion channels, and vice-versa. There is increasingly strong evidence that the activity of cardiac ion channels can influence the susceptibility of the heart to arrhythmias, infarction, and mechanical dysfunction. By identifying mechanistic “players” in these pathways, we hope to learn more about better prevention and treatment. Two of these players are briefly discussed below.

ATP-sensitive potassium channels: Linking the metabolic state of the heart to the electrical state of the heart. Several isoforms of potassium channels in the sarcolemmal membrane are sensitive to ATP levels; these ion channels are called ATP-sensitive (KATP) channels. When ATP levels in the subcellular compartments drop, KATP channels open and potassium conductance increases. Our previous work has demonstrated that increased expression and activity of KATP channels is linked to cardioprotection. Exactly how KATP channels can protect heart tissue remains to be elucidated, and is an on-going focus of our group.

Mitochondrial benzodiazepine receptors: “First responders” to oxidative stress. Ischemia/Reperfusion injury is first and foremost a disease of the mitochondria. Oxygen is required as the final electron acceptor in the mitochondrial redox reactions, and mitochondria are also the major producer of rective oxygen species (ROS). Under conditions of metabolic stress (ischemia), mitochondria quickly lose their membrane potential. When oxygen is restored (reperfusion), mitochondria repolarize quickly but produce a burst of ROS that is a major cause of reperfusion injury. One ion channel in particular – the mitochondrial benzodiazepine receptor – appears to conduct superoxide anion and we have shown that this receptor can contribute to the onset of arrhythmia in the intact heart. Our future research seeks to more clearly identify the role of the mBzR in ischemia/reperfusion, with a particular focus on how this ion channel is altered disease (diabetes).

Assistant Professor (October 2008 – Present)
Department of Physiology
Brody School of Medicine
East Carolina University
Greenville, NC

Post-Doctoral Fellow (February 2006 – September 2008 )
Institute of Molecular Cardiobiology
Division of Cardiology, Department of Medicine
The Johns Hopkins University School of Medicine
Baltimore, MD
Mentor: Dr. Brian O’Rourke

Doctor of Philosophy (Integrative Physiology)
University of Colorado at Boulder; Boulder, CO 2005
Dissertation Title: “Myocardial ATP-sensitive Potassium Channels and Ischemia/Reperfusion Injury”.
Ph.D. Advisor: Dr. Russell L. Moore

Research Consultant (Sep. 2003 – May 2004)
Myogen Pharmaceuticals
Westminster, CO

Editorial Assistant (Aug. 1999 – Aug. 2000)
Journal of Applied Physiology

Bachelor of Science (Exercise Science)
Virginia Tech; Blacksburg, VA 1999
Cum Laude
Minor: Chemistry

David A. Brown and Wayne E. Cascio. ‘Leaky’ Ryanodine Receptors and Sudden Cardiac Death. Cardiovascular Research 2009 (in press; doi: 10.1093/cvr/cvp330).

Aon Miguel A., Sonia Cortassa, Fadi G. Akar, David A. Brown, Lufang Zhou, and Brian O’Rourke. From Mitochondrial Dynamics To Arrhythmias. International Journal of Biochemistry and Cell Biology 2009 (in press).

Brown David A., Miguel A. Aon, Fadi G. Akar, Nicolas Sorarrain, and Brian O’Rourke. Effects of 4`-chlorodiazepam on Cellular Excitation-Contraction Coupling and Ischemia-Reperfusion Injury in Rabbit Heart. Cardiovascular Research 2008; 79: 141-149.

Brown David A., Micah S. Johnson, Casey J. Armstrong, Nicholas M. Caruso, Lindsay B. Ehlers, Joshua M. Lynch, Monika Fleshner, Robert Spencer, and Russell L. Moore. Short-term treadmill running in the rat: what kind of stressor is it? Journal of Applied Physiology 2007; 103: 1979-1985.

Brown David A. and Russell L. Moore. Perspectives in Innate and Acquired Cardioprotection Mini-Review Series: Cardioprotection Acquired Through Exercise. Journal of Applied Physiology 2007; 103(5): 1894-9.

Johnson Micah S., Russell L. Moore, and David A. Brown. Sex differences in myocardial infarct size are abolished by sarcolemmal KATP channel blockade in rat. American Journal of Physiology: Heart and Circulatory Physiology 2006; 290: H2644-H2647.

Brown David A., Adam J. Chicco, Korinne N. Jew, Micah S. Johnson, Joshua M. Lynch, and Russell L. Moore. Cardioprotection afforded by chronic exercise training is mediated by the sarcolemmal, and not the mitochondrial, isoform of the KATP channel. Journal of Physiology 2005; 569.3: 913–924.

Brown David A., Joshua M. Lynch, Casey J. Armstrong, Nicholas M. Caruso, Lindsay B. Ehlers, Micah S. Johnson, and Russell L. Moore. Susceptibility of the heart to ischaemia-reperfusion injury and exercise-induced cardioprotection are sex-dependent in the rat. Journal of Physiology 2005; 564.2: 619-630.

Brown David A., Korinne N. Jew, Genevieve C. Sparagna, Timothy I. Musch, Russell L. Moore. Exercise training reduces infarct size following transient coronary artery occlusion in the rat. Journal of Applied Physiology 2003; 95 (6): 2510-8.

“Best Should Teach” Award, University of Colorado, 2004
Research Recognition Award, Cardiovascular Section of the American Physiological Society, 2004
Gatorade Young Investigator Award, Environmental and Exercise Physiology Section, American Physiological Society, 2005
Mr. and Mrs. J. Tour Scholar, University of Colorado, 2005