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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL104126-04
Application #
8286370
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Goldberg, Suzanne H
Project Start
2010-08-15
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$371,250
Indirect Cost
$123,750
Name
Georgia Regents University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Bagi, Zsolt (2015) Impaired coronary collateral growth: miR-shaken neutrophils caught in the act. Am J Physiol Heart Circ Physiol 308:H1321-2
Czikora, Istvan; Feher, Attila; Lucas, Rudolf et al. (2015) Caveolin-1 prevents sustained angiotensin II-induced resistance artery constriction and obesity-induced high blood pressure. Am J Physiol Heart Circ Physiol 308:H376-85
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
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
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
Chen, Feng; Barman, Scott; Yu, Yanfang et al. (2014) Caveolin-1 is a negative regulator of NADPH oxidase-derived reactive oxygen species. Free Radic Biol Med 73:201-13
Czikora, István; Alli, Abdel; Bao, Hui-Fang et al. (2014) A novel tumor necrosis factor-mediated mechanism of direct epithelial sodium channel activation. Am J Respir Crit Care Med 190:522-32
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
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
Broskova, Zuzana; Sotnikova, Ruzena; Nedelcevova, Jana et al. (2013) Effect of a novel stobadine derivative on isolated rat arteries. Interdiscip Toxicol 6:63-6

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