Membrane phospholipids play a crucial role in the pathophysiology of myocardial ischemic reperfusion injury. During the tenure of this proposal, it has become apparent that reperfusion of ischemic myocardium potentiates intracellular signaling via the activation of phospholipase C and D leading to the translocation and activation of multiple kinases including protein kinase C and MAPKAP kinase 2. Activation of kinases results in the induction of the expression of a variety of genes which play a significant role in the survival of the postischemic myocytes. As a spin off of this research, a novel role of phospholipids has become evidence, i.e., reperfusion of ischemic myocardium induces apoptosis, and membrane phospholipids are likely to play a significant role in the mechanism of the apoptotic cell death. The current proposal is based on this novel finding and represents a logical step for the continuing investigation. This proposed research will explore the role of phospholipids in reperfusion apoptosis by addressing the following specific aims: (i) down-regulation of aminophospholipid translocase and upregulation of lipid scramblase leading to the translocation of phosphatidylserine from the inner leaflet to the outer leaflet; (ii) reperfusion-mediated increase in cytosolic Ca2+ and free radicals in apoptotic cell death; (iii) relative importance of sphingnomyelin-sphingnosine-ceramide signaling and diacylglvcererol-protein kinase C/cyclin-dependent kinases signaling; and (iv) examine the regulation of inducer (Bax,Abl, fas, c-fos, c-myc) and repressor (bcl-2) genes (for apoptosis) in reperfusion injury and develop approaches to modulate induction of these genes in an attempt to reduce ischemia reperfusion injury. Since bcl-2 has been demonstrated as anti-death gene for apoptosis, transgenic mice over-expressing bcl-2 gene will be used to examine the altered signal transduction mechanism which could regulate apoptosis and responsible for the reduction of ischemic reperfusion injury. The ultimate goal of this investigation is to develop modalities to block apoptosis during reperfusion of the ischemic heart, which will hopefully ameliorate reperfusion injury.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Surgery and Bioengineering Study Section (SB)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Connecticut
Schools of Medicine
United States
Zip Code
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
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
Lekli, Istvan; Ray, Diptarka; Mukherjee, Subhendu et al. (2010) Co-ordinated autophagy with resveratrol and ?-tocotrienol confers synergetic cardioprotection. J Cell Mol Med 14:2506-18

Showing the most recent 10 out of 185 publications