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.
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.
|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|
|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|