Travis W. Hein, Ph.D.
Assistant Professor
Department of Surgery
Education
- B.A. - St. Olaf College, Northfield, Minnesota.
Major field: Biology. (May 1992). - Ph.D. - Texas A&M University System Health Science Center
College Station, Texas.
Major field: Medical Sciences.
Mentor: Dr. Lih Kuo.
Dissertation Title: “Low-density lipoproteins impair coronary arteriolar function.” (August 1997). - Postdoctoral Training - Texas A&M University System Health Science Center.
Field of Study: Cardiovascular Physiology, Microcirculatory Control.
Mentors: Drs. Lih Kuo and Mariappan Muthuchamy (September 1997-August 1999).
Hein TW, Kuo L. LDLs impair vasomotor function of the coronary microcirculation: role of superoxide anions. Circ Res. 83:404-414, 1998.
Hein TW, Kuo L. cAMP-independent dilation of coronary arterioles to adenosine: role of nitric oxide, G proteins, and KATP channels. Circ Res. 85:634-642, 1999.
Hein TW, Liao J, Kuo L. Oxidized LDL specifically impairs endothelium dependent, NO-mediated dilation of coronary arterioles. Am J Physiol. 278:H175-H183, 2000.
Hein TW, Wang W, Zoghi B, Muthuchamy M, Kuo L. Functional and molecular characterization of receptor subtypes mediating microvascular dilation to adenosine. J Mol Cell Cardiol. 33:271-282, 2001.
Rivers R, Hein TW, Zhang C, Kuo L. Activation of barium-sensitive inward rectifier potassium channels mediates remote dilation of coronary arterioles. Circulation. 104:1749-1753, 2001.
Zhang C, Hein TW, Wang W, Chang C-I, Kuo L. Constitutive expression of arginase in coronary microvascular endothelial cells counteracts nitric oxide-mediated vasodilatory function. FASEB J. (March 12, 2001) 10.1096/fj.00-0681fje (http://www.fasebj.org/cgi/doi/10.1096/fj.00-0681fje); FASEB J. 15:1264-1266, 2001.
Hein TW, Zhang C, Wang W, Chang C-I, Thengchaisri N, Kuo L. Ischemia-reperfusion selectively impairs nitric oxide-mediated dilation in coronary arterioles: counteracting role of arginase. FASEB J. (October 16, 2003) 10.1096/fj.03-0115fje (http://www.fasebj.org/cgi/doi/10.1096/fj.03-0115fje); FASEB J. 17:2328-2330, 2003.
Blood flow in the coronary and retinal circulation is closely regulated to meet the metabolic demands of the heart and retina, respectively. Since vascular resistance resides predominantly in the microvessels, alterations in the diameter of these vessels are largely responsible for matching metabolic needs. My research focuses on understanding the mechanisms involved in the metabolic control of vascular tone in the coronary and retinal microvessels under physiological and pathophysiological conditions. Current approaches used to comprehensively study vascular regulatory mechanisms in the microcirculation include isolated and perfused microvessels, cultured endothelial and smooth muscle cells, immunohistochemistry, and biochemical and molecular techniques. I have previously addressed the cellular mechanism of coronary arteriolar dilation to the potent metabolic vasodilator adenosine under physiological conditions using functional (isolated, perfused arterioles), pharmacological, biochemical, and molecular tools (Circ Res. 85:634-642, 1999; J Mol Cell Cardiol. 33:271-282, 2001). I demonstrated that adenosine-induced coronary arteriolar dilation is mediated by the activation of endothelial and smooth muscle A2A receptors, which leads to the stimulation of the G-protein-dependent endothelial nitric oxide pathway and to the opening of smooth muscle ATP-sensitive K+ (KATP) channels. In contrast to the conventional belief in large conduit arteries, the dilation of coronary arterioles to adenosine is independent of cAMP signaling. Our preliminary studies in the retinal microcirculation indicate that retinal arterioles also dilate in response to adenosine via the activation of A2A receptors and subsequent opening of KATP channels. Furthermore, my colleagues and I have shown that the coronary arterioles exhibit a conducted vasodilatory response (i.e., dilation elicited at one location can be transmitted to the remote sites) in response to metabolic vasodilators, including adenosine, K+, and bradykinin, via activation of inward rectifier K+ (Kir) channels (Circulation. 104:1749-1753, 2001). The possible role of Kir2 channels and their underlying signaling mechanism in this vasodilatory response is currently being investigated in my lab.
Under pathophysiological conditions such as atherosclerosis, ischemia-reperfusion injury and elevated intraocular pressure, the vascular blood flow regulation is impaired due, in part, to the dysfunction of endothelium-dependent nitric oxide-mediated vasodilation. Two potential mechanisms for this vascular dysfunction are increased production of reactive oxygen species, such as superoxide anion, and a reduction in the intracellular levels of L-arginine, the nitric oxide precursor. However, the underlying mechanisms remain to be unequivocally established. Our previous studies suggest that the atherogenic factor oxidized low-density lipoprotein specifically impairs coronary arteriolar dilation to endothelium-dependent NO-mediated agonists such as adenosine and serotonin (Circ Res. 83:404-414, 1998; Am J Physiol. 278:H175-H183, 2000) by increasing vascular production of superoxide anion. In addition, my colleagues and I provided the first evidence that constitutive expression of arginase I, an L-arginine consuming enzyme, in endothelial cells counteracts nitric oxide-dependent dilation of coronary microvessels (FASEB J. 15:1264-1266, 2001). The results from this study suggest a novel pathway for modulating nitric oxide production in coronary microvessels. This fundamental information has been extended to the pathophysiological condition of ischemia and reperfusion where we have shown recently shown that the upregulation of vascular arginase during this vascular insult can impair nitric oxide-mediated dilation of coronary arterioles (FASEB J. 17:2328-2330, 2003). We have also generated some preliminary data showing that the nitric oxide-mediated dilation of retinal arterioles is impaired by an acute elevation of intraocular pressure. It appears that an increased oxidative stress (i.e., superoxide production) contributes to this vascular dysfunction because administration of a superoxide scavenger restores arteriolar function. We are currently examining the possible role of superoxide-generating enzymes and their vascular cell sources in this retinal microvascular dysfunction.
We expect that the information gleaned from our studies could provide a better understanding of the local metabolic regulatory mechanisms of coronary and retinal microvascular tone during normal and disease states. Such outcomes will be significant because this new knowledge will suggest novel targets for therapeutic interventions that will be important to patients with coronary and/or retinal vascular dysfunction.
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