Patients with type 2 diabetes mellitus (T2-DM) have higher prevalence of no-reflow phenomenon - a poorly understood and unpredictable complication of percutaneous coronary intervention (PCI) in which diminished blood flow to distal microvascular beds persists despite the successful treatment of the occlusive lesion of the epicardial coronary artery. Current therapeutic interventions to prevent no reflow are ineffective. Preliminary observations related to this application led to my main hypothesis that small coronary arteries of diabetic patients exhibit a paradoxical constriction to sudden increases in flow, an alteration, which contributes to no reflow. I propose that RhoA-dependent co-localization of arginase I and eNOS leads to reduced NO synthesis and diminished NO-mediated dilatation in response to flow in T2-DM. I also hypothesize that stimulation of platelet endothelium cell adhesion molecule -1 (Pecam-1, known as primary flow sensor in endothelium) with increases in intraluminal flow elevates endothelial [Ca2+]i, which via inducing phospholipase A2 and arachidonic acid release leads to enhanced production of thromboxane A2 in coronary vessels of T2-DM patients. To test these hypotheses, I aim to isolate small coronary vessels from the (discarded) atrial appendages of patients with T2-DM undergoing cardiac surgery. Using small vessel pressure myography and videomicroscopy, diameter changes of the isolated, coronary arteriole (<100 5m) exposed to sudden increase in intraluminal flow will be measured in the presence of inhibitors of specific signaling pathways. To investigate (co)localization of eNOS and arginase I as well as to detect spatial distribution and interaction of Pecam-1 laser scanning confocal microscopy and fluorescence resonance energy transfer approaches will be used in isolated, pressurized coronary arteries and coronary endothelial cells in culture. Moreover, flow-induced changes in endothelial [Ca2+]i will be measured with Fura-2 fluorescence in intact, pressurized coronary arterioles to reveal spatial differences of [Ca2+]i elevations at subcellular level. Should the results obtained in the course of the project support my hypothesis this will be the first description of Pecam-1-coupled constrictor prostanoid production in human coronary arteries. Results will also provide a novel mechanism by which spatial distribution of Pecam-1 determines the nature of vasoactive mediators released to increase in flow in T2-DM. Data obtained in this project will also help to develop novel avenues for effective therapeutic strategies, such as the use of prostanoid inhibitors at the time of PCI, to prevent no reflow in patients with T2-DM.

Public Health Relevance

This proposal seeks to support research to elucidate mechanism(s), which may contribute to coronary no- reflow, a serious complication of percutaneous coronary intervention in having higher prevalence in diabetic patients.
I aim to isolate small coronary vessels from the (discarded) atrial appendages of diabetic patients undergoing cardiac surgery. Using this approach the proposal aims to provide a rationale for effective therapeutic intervention to prevent no reflow in diabetic patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Goldberg, Suzanne H
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Georgia Regents University
Internal Medicine/Medicine
Schools of Medicine
United States
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Cassuto, James; Dou, Huijuan; Czikora, Istvan et al. (2014) Peroxynitrite disrupts endothelial caveolae leading to eNOS uncoupling and diminished flow-mediated dilation in coronary arterioles of diabetic patients. Diabetes 63:1381-93
Bagi, Zsolt; Broskova, Zuzana; Feher, Attila (2014) Obesity and coronary microvascular disease - implications for adipose tissue-mediated remote inflammatory response. Curr Vasc Pharmacol 12:453-61
Feher, Attila; Broskova, Zuzana; Bagi, Zsolt (2014) Age-related impairment of conducted dilation in human coronary arterioles. Am J Physiol Heart Circ Physiol 306:H1595-601
Cassuto, James; Feher, Attila; Lan, Ling et al. (2013) Obesity and statins are both independent predictors of enhanced coronary arteriolar dilation in patients undergoing heart surgery. J Cardiothorac Surg 8:117
Koller, Akos; Balasko, Marta; Bagi, Zsolt (2013) Endothelial regulation of coronary microcirculation in health and cardiometabolic diseases. Intern Emerg Med 8 Suppl 1:S51-4
Feher, Attila; Cassuto, James; Szabo, Andras et al. (2013) Increased tissue angiotensin-converting enzyme activity impairs bradykinin-induced dilation of coronary arterioles in obesity. Circ J 77:1867-76
Huang, An; Yang, Yang-Ming; Feher, Attila et al. (2012) Exacerbation of endothelial dysfunction during the progression of diabetes: role of oxidative stress. Am J Physiol Regul Integr Comp Physiol 302:R674-81
Beleznai, Timea; Bagi, Zsolt (2012) Activation of hexosamine pathway impairs nitric oxide (NO)-dependent arteriolar dilations by increased protein O-GlcNAcylation. Vascul Pharmacol 56:115-21
Bagi, Zsolt; Feher, Attila; Cassuto, James (2012) Microvascular responsiveness in obesity: implications for therapeutic intervention. Br J Pharmacol 165:544-60
Bagi, Zsolt; Feher, Attila; Cassuto, James et al. (2011) Increased availability of angiotensin AT 1 receptors leads to sustained arterial constriction to angiotensin II in diabetes - role for Rho-kinase activation. Br J Pharmacol 163:1059-68

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