This proposal is a continuation of 11 years of research whose goal has been the developing of an understanding of the pathophysiologic process of myocardial ischemia and reperfusion. In this project we are going to concentrate on analyzing the significance of calcium accumulation in the myocyte during ischemia and reperfusion. Calcium flux will be correlated with the degree of myocardial injury in the in-situ isolated pig heart model (30 min regional LAD ischemia), the intact pig (60 min LAD ischemia), and the Langendorff-perfused rat heart model (30 min global ischemia). The parameters measured will assess changes at the global [contractility and compliance, coronary blood flow, myocardial O2 consumption and extraction, creatine kinase release, malonaldehyde and hydroxyl radical generation], regional [contractility and infarct size], cellular [high energy phosphate levels, lipid peroxidation products, phospholipids and their degradation products, and hydroxyl radical formation] and subcellular [sarcolemmal membrane function and Ca2+ release from sarcoplasmic reticulum] levels. Calcium concentration will be determined using atomic absorption spectroscopy to measure total myocardial [Ca2+] in the pig heart, and intracellular [Ca2+] will be studied using a new approach involving fluorescent spectroscopy in the rat heart. This latter method evaluates [Ca2+] with a fluorescent probe, FURA-2AM, in the Langendorff mode. Specific interventions designed to study aspects of Ca2+ accumulation will be studies. These will include a determination of the mechanism of Ca2+ accumulation by selective inhibition of the calcium show channels, Na+/Ca2+ and Na+/H+ exchange, and Ca2+/calmodulin receptors. The significance of phospholipase and kinase activation and inositol 1, 3, 5 triphosphate will be studied in regard to Ca2+ accumulation and myocardial injury. Associated with ischemia and reperfusion, we have previously shown that free radical generation, phospholipase activation, and phospholipid degradation occur in concert. The relationship between the ionophoretic products of phospholipid degradation and Ca2+ uptake will be assessed. Hormonal influences such as triiodothyronine and atrial natriuretic factor will be evaluated as a factor in the Ca2+ extrusion mechanism as will the application of angiotensin converting enzyme inhibition. New approaches to assessing Ca2+ flux, specifically intracellular pH and membrane redox potential will be studied as well. The influence of intracellular ca2+ on arrhythmogenicity will be examined. Finally, optimal combination therapies will be developed to provide improved control of Ca2+ flux, and these interventions will be correlated with the parameters of preservation already described. Using the agents defined as """"""""optimal"""""""", the intact pig subjected to regional LAD (60 min) ischemia will be studied to measure preservation of stunned myocardium and reduction of infarct size.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Surgery and Bioengineering Study Section (SB)
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University of Connecticut
Schools of Medicine
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Das, Somak; Mitrovsky, Goran; Vasanthi, Hannah R et al. (2014) Antiaging properties of a grape-derived antioxidant are regulated by mitochondrial balance of fusion and fission leading to mitophagy triggered by a signaling network of Sirt1-Sirt3-Foxo3-PINK1-PARKIN. Oxid Med Cell Longev 2014:345105
Das, Somak; Mukherjee, Subhendu; Lekli, Istvan et al. (2012) Tocotrienols confer resistance to ischemia in hypercholesterolemic hearts: insight with genomics. Mol Cell Biochem 360:35-45
(2012) Retraction. Freshly crushed garlic is a superior cardioprotective agent than processed garlic. J Agric Food Chem 60:2766
Mukhopadhyay, Partha; Pacher, Pal; Das, Dipak K (2011) MicroRNA signatures of resveratrol in the ischemic heart. Ann N Y Acad Sci 1215:109-16
Das, Dipak K; Mukherjee, Subhendu; Ray, Diptarka (2011) Erratum to: resveratrol and red wine, healthy heart and longevity. Heart Fail Rev 16:425-35
Juhasz, Bela; Juhaz, Bela; Das, Dipak K et al. (2011) Reduction of blood cholesterol and ischemic injury in the hypercholesteromic rabbits with modified resveratrol, longevinex. [corrected] Mol Cell Biochem 348:199-203
Gurusamy, Narasimman; Lekli, Istvan; Ahsan, Md Kaimul et al. (2010) Downregulation of cardiac lineage protein-1 confers cardioprotection through the upregulation of redox effectors. FEBS Lett 584:187-93
Das, Dipak K; Mukherjee, Subhendu; Ray, Diptarka (2010) Resveratrol and red wine, healthy heart and longevity. Heart Fail Rev 15:467-77
Vasanthi, Hannah Rachel; Mukherjee, Subhendu; Ray, Diptarka et al. (2010) Protective role of air potato (Dioscorea bulbifera) of yam family in myocardial ischemic reperfusion injury. Food Funct 1:278-83
Gurusamy, Narasimman; Lekli, Istvan; Mukherjee, Subhendu et al. (2010) Cardioprotection by resveratrol: a novel mechanism via autophagy involving the mTORC2 pathway. Cardiovasc Res 86:103-12

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