Acute hyperglycemia is independently associated with larger myocardial infarct (MI) size and impaired LV function in both diabetic and non-diabetic patients. However, the mechanisms underlying the exacerbation of myocardial injury by acute hyperglycemia remain unclear, especially in non-diabetics. Acute hyperglycemia is associated with increased oxidative stress, endothelial dysfunction, activation of coagulation and enhanced inflammation. Our preliminary studies show that acute hyperglycemia, induced shortly before ischemia in non- diabetic mice, significantly enhances reperfusion injury and abolishes both ischemic pre- and post-conditioning. Furthermore, we have shown that activation of Adenosine 2A Receptors (A2AR) with a specific agonist immediately before reperfusion abrogates the hyperglycemic exacerbation of myocardial injury, as does treatment with the potent antioxidant MPG. These studies indicate that acute hyperglycemia in non-diabetics increases the size of MI by interrupting endogenous cardioprotective mechanisms, increasing oxidative stress and provoking innate inflammatory responses. Growing evidence now indicates that the formation of advanced glycated end products (AGEs) during acute hyperglycemia plays a central role in exacerbating MI size through their interaction with the AGE receptor (RAGE). Our previous work showed that A2ARs on CD4+ T cells play a critical role in regulating the inflammatory responses that contribute importantly to MI size, and that infarct size is reduced by activating A2ARs prior to reperfusion. Our preliminary studies show that activation of A2ARs also prevents the hyperglycemic exacerbation of myocardial injury. We therefore hypothesize that acute hyperglycemia exacerbates infarct size by enhancing CD4+ T cell-mediated innate immune responses via RAGE stimulation and increasing oxidative stress. To test the hypothesis in vivo, we will use a mouse model of myocardial ischemia/reperfusion injury with acute hyperglycemia to address the following specific aims: 1) Determine the mechanistic roles of oxidative stress, the AGE/RAGE axis and glucose normalization with insulin in the hyperglycemic exacerbation of myocardial infarct (MI) size.
This Aim will be pursued by applying specific pharmacologic probes (potent antioxidants, AGE inhibitors, soluble RAGE and insulin) in the murine model of MI, then assessing their impact on infarct size and post-reperfusion inflammatory responses. 2) Determine the identity of the cell types carrying the AGE, A2A and IL-18 receptors that mediate and regulate the hyperglycemic exacerbation of infarct size in vivo.
This aim will employ an array of knockout mice (CD4- null, RAGE-null, A2AR-null &IL18R-null) to test the hypothesis that the presence of each of these receptors on CD4+ T cells plays a critical role in mediating/regulating the deleterious effects of hyperglycemia on MI size. 3) Apply the mechanistic insights gleaned from Aims 1 &2 to identify a clinically-relevant treatment strategy capable of minimizing MI size in euglycemic/hyperglycemic mice and confirm that this has an enduring, positive impact on LV structure and function using cutting-edge techniques in cardiac MRI.

Public Health Relevance

Ischemic heart disease remains the single leading cause of death in the United States, accounting for fully one out of every five deaths. Myocardial infarction (heart attack) and heart failure resulting from heart attack account for the vast majority of the death and illness associated with ischemic heart disease. Some people have high blood sugar (hyperglycemia) when they experience a heart attack, even if they have no prior history of high blood sugar. These patients die from their heart attack much more often than patients without high blood sugar. This research project will increase our understanding of why high blood sugar worsens clinical outcome in patients with heart attack, and will identify the best combination of new and existing drugs to reduce the size of heart attack in patients with (and without) high blood sugar.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL092305-05
Application #
8495393
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Wong, Renee P
Project Start
2009-08-01
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$356,914
Indirect Cost
$121,294
Name
University of Virginia
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
Tian, Yikui; Piras, Bryan A; Kron, Irving L et al. (2015) Adenosine 2B Receptor Activation Reduces Myocardial Reperfusion Injury by Promoting Anti-Inflammatory Macrophages Differentiation via PI3K/Akt Pathway. Oxid Med Cell Longev 2015:585297
Tian, Yikui; Marshall, Melissa; French, Brent A et al. (2015) The infarct-sparing effect of IB-MECA against myocardial ischemia/reperfusion injury in mice is mediated by sequential activation of adenosine A3 and A 2A receptors. Basic Res Cardiol 110:16
Tian, Yikui; French, Brent A; Kron, Irving L et al. (2015) Splenic leukocytes mediate the hyperglycemic exacerbation of myocardial infarct size in mice. Basic Res Cardiol 110:39
Yang, Zequan; Tian, Yikui; Liu, Yuan et al. (2013) Acute hyperglycemia abolishes ischemic preconditioning by inhibiting Akt phosphorylation: normalizing blood glucose before ischemia restores ischemic preconditioning. Oxid Med Cell Longev 2013:329183
Konkalmatt, Prasad R; Beyers, Ronald J; O'Connor, Daniel M et al. (2013) Cardiac-selective expression of extracellular superoxide dismutase after systemic injection of adeno-associated virus 9 protects the heart against post-myocardial infarction left ventricular remodeling. Circ Cardiovasc Imaging 6:478-86
Konkalmatt, Prasad R; Wang, Feng; Piras, Bryan A et al. (2012) Adeno-associated virus serotype 9 administered systemically after reperfusion preferentially targets cardiomyocytes in the infarct border zone with pharmacodynamics suitable for the attenuation of left ventricular remodeling. J Gene Med 14:609-20
Beyers, Ronald J; Smith, R Scott; Xu, Yaqin et al. (2012) Tâ‚‚ -weighted MRI of post-infarct myocardial edema in mice. Magn Reson Med 67:201-9
Laubach, Victor E; French, Brent A; Okusa, Mark D (2011) Targeting of adenosine receptors in ischemia-reperfusion injury. Expert Opin Ther Targets 15:103-18
Prasad, Konkal-Matt R; Smith, Robert S; Xu, Yaqin et al. (2011) A single direct injection into the left ventricular wall of an adeno-associated virus 9 (AAV9) vector expressing extracellular superoxide dismutase from the cardiac troponin-T promoter protects mice against myocardial infarction. J Gene Med 13:333-41
Zhong, Xiaodong; Gibberman, Lauren B; Spottiswoode, Bruce S et al. (2011) Comprehensive cardiovascular magnetic resonance of myocardial mechanics in mice using three-dimensional cine DENSE. J Cardiovasc Magn Reson 13:83