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Johnathan Tune, Ph.D.

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Professor 
Full Member of Graduate Faculty
Graduate Program Director 
Department of Cellular & Integrative Physiology
Indiana University School of Medicine
635 Barnhill Drive, Room MS 2069
Indianapolis, Indiana 46202-5120 
E-mail: jtune@iu.edu
Phone: 317-274-3433
Facsimile: 317-274-3318

Research Biography Summary

Personal Statement

Research throughout my career has focused on the regulation of myocardial oxygen delivery, contractile function and metabolism in health and disease. My laboratory has been continuously funded for >15 years by the National Institutes of Health, the American Heart Association, the American Diabetes Association, as well as pharmaceutical companies with the primary focus of elucidating mechanisms of impaired coronary and cardiac function in the setting of obesity and diabetes. Our studies routinely include a series of experimental approaches utilizing both in vivo (chronically instrumented conscious and/or acute open-chest swine) and in vitro (isolated artery rings, pressurized arterioles, Western blot, RT-PCR, immunohistochemistry, confocal microscopy) methodologies to examine hypotheses in a highly integrative manner. These studies have led to >90 peer-reviewed publications and the successful training of numerous post-doctoral fellows, PhD, and MS students.

Honors

1998    Received Outstanding Graduate Award in Graduate School of Biomedical Sciences

2001    Awarded American Diabetes Association Career Development Award

2003    Outstanding Faculty Lecturer - UNTHSC

2010    Trustee Teaching Award IU School of Medicine

2011    Fellow, American Heart Association (Arterioscler Thromb Vasc Biol Section)

2011    Fellow, American Physiological Society (Cardiovascular Section)

2013    Trustee Teaching Award IU School of Medicine

2013    American Physiological Society - Henry Pickering Bowditch Award Lecturer

2014    Trustee Teaching Award IU School of Medicine

2015    Trustee Teaching Award IU School of Medicine

 

Contribution to Science (manuscripts; citations)

1.  Much of my research has focused on delineating putative mechanisms of coronary blood flow control in health and disease. Findings from these studies have provided seminal findings regarding the modest contribution of adenosine and nitric oxide to the physiologic regulation of myocardial oxygen supply/demand balance and in supporting the requisite role of coronary ion channels in modulating coronary microvascular resistance in response to changes in metabolism, myocardial ischemia, and alterations in coronary perfusion pressure. Representative publications of our work in this area include:

 a.  Tune JD, Richmond KN, Gorman MW, Olsson RA, Feigl EO. Adenosine is not responsible for local metabolic control of coronary blood flow in dogs during exercise. Am. J. Physiol. Heart Circ. Physiol. 278: H74-H84, 2000.

 b.  Tune JD, Richmond KN, Gorman MW, Feigl EO. Role of nitric oxide and adenosine in control of coronary blood flow in exercising dogs. Circulation 101: 2942-2948, 2000.

 c.  Dick GM, Bratz IN, Borbouse L, Payne GA, Dincer UD, Knudson JD, Rogers PA, Tune JD. Voltage-dependent K+ channels regulate the duration of reactive hyperemia in the canine coronary circulation. Am. J. Physiol. Heart Circ. Physiol. 294: H2371-H2381, 2008.

 d.  Berwick ZC, Moberly SP, Kohr MC, Morrical EB, Kurian MM, Dick GM, Tune JD. Contribution of voltage-dependent K+ and Ca2+ channels to coronary pressure-flow autoregulation. Basic Res. Cardiol. 107:1-11, 2012.

 2. A direct extension of my research on control of coronary blood flow has focused on examination of mechanisms of coronary vascular dysfunction in the setting of obesity, metabolic syndrome, and diabetes mellitus. These studies have demonstrated that obesity/diabetes markedly impair the ability of the coronary circulation to adequately balance myocardial oxygen delivery with myocardial metabolism at rest, during increases in cardiac metabolic demand, in response to changes in perfusion pressure, and following a brief episode of myocardial ischemia. Our findings indicate this impairment is related to a variety of mechanisms, including activation of the renin-angiotensin and sympathetic nervous system as well as alterations in specific ion channels which disrupt electromechanical coupling of coronary vascular smooth muscle. Important publications in this field include:

 a.  Tune JD, Yeh C, Setty S, Downey HF. ATP-dependent K+ channels contribute to local metabolic coronary vasodilation in experimental diabetes mellitus.  Diabetes 51: 1201-1207, 2002.

 b.  Zhang C, Knudson JD, Setty S, Araiza A, Dincer UD, Kuo L, Tune JD. Coronary arteriolar constriction to angiotensin II is augmented in the prediabetic metabolic syndrome via activation of AT1 receptors.  Am. J. Physiol. Heart Circ. Physiol. 288: H2154-H2162, 2005.

 c.  Borbouse L, Dick GM, Asano S, Bender SB, Dincer UD, Payne GA, Neeb ZP, Bratz IN, Sturek M, Tune JD. Impaired function of coronary BKCa channels in metabolic syndrome. Am. J. Physiol. Heart Circ. Physiol. 297: H1629-H1637, 2009.

 d.  Berwick ZC, Dick GM, O’Leary HA, Bender SB, Goodwill AG, Moberly SP, Owen MK, Obukhov AG, Tune JD. Contribution of electromechanical coupling between KV and CaV1.2 channels to coronary dysfunction in metabolic syndrome. Basic Res Cardiol. 108:370, 2013.

 3. My laboratory has been on the forefront of research to examine mechanisms by which adipocyte-derived cytokines contribute to the initiation and progression of obesity-induced coronary dysfunction and disease. Findings from these studies implicate adipokines as a key molecular link between obesity and cardiovascular disease. In particular, our initial studies demonstrated that the adipokines leptin and resistin significantly impair coronary endothelial-dependent vasodilation via inhibition of coronary nitric oxide (NO) production. We recently extended these findings to discover that coronary perivascular adipose tissue is uniquely capable of potentiating coronary smooth muscle contraction and diminishing coronary endothelial dependent and independent vasodilation. Importantly, these effects of perivascular adipose derived factors are augmented in the setting of obesity and are directly associated with substantial alterations in the perivascular genome and proteome. Key studies in this emerging area of research include:

 a.  Knudson JD, Dincer UD, Zhang C, Swafford AN, Koshida R, Picchi A, Focardi M, Dick GM, Tune JD. Leptin receptors are expressed in coronary arteries and hyperleptinemia causes significant coronary endothelial dysfunction. Am. J. Physiol. Heart Circ. Physiol. 289: H48-H56, 2005.

 b.  Payne GA, Borbouse L, Kumar S, Neeb Z, Alloosh M, Sturek M, Tune JD. Epicardial perivascular adipose-derived leptin exacerbates coronary endothelial dysfunction in metabolic syndrome via a PKC-b pathway. Arterioscler Thromb. Vasc. Biol. 30: 1711-1717, 2010.

 c.  Owen MK, Witzmann FA, McKenney ML, Lai X, Berwick ZC, Moberly SP, Alloosh M, Sturek M, Tune JD. Perivascular adipose tissue potentiates contraction of coronary vascular smooth muscle: Influence of obesity. Circulation 128:9-18, 2013.

 d.  Noblet JN, Owen MK, Goodwill AG, Sassoon DJ, Tune JD. Lean and obese coronary perivascular adipose tissue impairs vasodilation via differential inhibition of vascular smooth muscle K+ channels. Arterioscler Thromb Vasc Biol. 35:1393-1400, 2015.

 4. Throughout my career I have maintained an interest in research to investigate cardioprotective mechanisms of metabolic modulation of cardiac intermediary metabolism. Early studies focused on metabolic mechanisms by which glucose and insulin influence cardiac contractile function and myocardial energetics in the setting of moderate ischemia. More recently, our work has centered directly on determining the cardiometabolic effects of glucagon like peptide-1 (GLP-1). Our findings are the first to demonstrate marked attenuation of GLP-1 mediated increases in myocardial glucose uptake in obese type 2 diabetic humans and swine and that this “resistance” to GLP-1 is related to impaired activation of p38 MAPK signaling. Additional data support that short-term systemic treatment with GLP-1 improves cardiac function during regional myocardial ischemia in lean-control swine via increases in ventricular preload without changes in cardiac inotropy (i.e. Frank-Starling mechanism). Representative publications of our research in this area include:

 a.  Tune JD, Mallet RT, Downey HF. Insulin improves contractile function during moderate ischemia in canine left ventricle. Am. J. Physiol. Heart Circ. Physiol. 275: H1574-H1581, 1998.

 b.  Tune JD, Mallet RT, Downey HF. Insulin improves cardiac contractile function and oxygen utilization efficiency during moderate ischemia without compromising myocardial energetics. J. Mol. Cell Cardiol. 30: 2025-2035, 1998.

 c.  Moberly SP, Mather KJ, Berwick ZC, Owen MK, Goodwill AG, Casalini ED, Hutchins GD, Green MA, Ng Y, Considine RV, Perry KM, Chisholm RL, Tune JD. Impaired cardiometabolic responses to glucagon-like peptide 1 in obesity and type 2 diabetes mellitus. Basic Res Cardiol. 108:365, 2013

 d.  Goodwill AG, Tune JD, Noblet JN, Conteh AM, Sassoon D, Casalini ED, Mather KJ. Glucagon like peptide-1 (7-36) but not (9-36) augments cardiac output during myocardial ischemia via a Frank-Starling mechanism. Basic Res. Cardiol. 109:426, 2014.

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