The application proposes to continue examining the molecular and cellular mechanisms of ischemic preconditioning (PC). During the current years' funding we demonstrated the role of multiple kinases including receptor tyrosine Idnases and stress-regulated mitogen-activated protein kinases in PC and established an essential role of nuclear transcriptional factor NFkappaB. Our studies also demonstrated that PC potentiates a survival signal by activating several anti-apoptotic genes and transcription factors simultaneously blocking the proapoptotic factors leading to the inhibition of apoptosis, which is now showed to independently contribute to myocardial infarction. While, PC has been proven to be the most powerful and state-of-the-art technique for cardioprotection, its clinical applicability is limited. Not only very limited studies exist in the literature to determine if PC could protect diseased hearts, the results are also confusing. We, therefore, propose to study if the cardioprotective abilities of PC are equally applicable to diseased hearts. We selected three most problematic diseased states: cardiomyopathy, hypertension and atherosclerosis which were found relatively less responsive to PC stimulus. We have already established our models to study these diseased hearts. Since adenosine, protein kinase C, protein tyrosine kinase, MAP kinases and KATP channels are the principle regulators for PC; we plan to determine the status of these factors in the diseased hearts. We anticipate inherent problems in one or more of these factors; and we will attempt to correct the deficiency by exogenous supplementation or by devising means to augment the deficient factors. We also anticipate reduced cardiac defense system in the diseased hearts, which consist of several intraceliular antioxidants and heat shock proteins. Again, we will attempt to precondition these hearts by devising methods to augment these defense elements. Our ultimate objective is to apply the preconditioning modality to protect diseased hearts which are resistant to preconditioning stimulus.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056803-08
Application #
7008906
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Schwartz, Lisa
Project Start
1998-02-01
Project End
2008-01-14
Budget Start
2006-02-01
Budget End
2008-01-14
Support Year
8
Fiscal Year
2006
Total Cost
$353,981
Indirect Cost
Name
University of Connecticut
Department
Surgery
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Joshi, Mandip; Kotha, Sainath R; Malireddy, Smitha et al. (2014) Conundrum of pathogenesis of diabetic cardiomyopathy: role of vascular endothelial dysfunction, reactive oxygen species, and mitochondria. Mol Cell Biochem 386:233-49
Thirunavukkarasu, Mahesh; Selvaraju, Vaithinathan; Dunna, Nageswara Rao et al. (2013) Simvastatin treatment inhibits hypoxia inducible factor 1-alpha-(HIF-1alpha)-prolyl-4-hydroxylase 3 (PHD-3) and increases angiogenesis after myocardial infarction in streptozotocin-induced diabetic rat. Int J Cardiol 168:2474-2480
Thirunavukkarasu, Mahesh; Adluri, Ram Sudheer; Juhasz, Bela et al. (2012) Novel role of NADPH oxidase in ischemic myocardium: a study with Nox2 knockout mice. Funct Integr Genomics 12:501-14
Adluri, Ram Sudheer; Thirunavukkarasu, Mahesh; Zhan, Lijun et al. (2011) Thioredoxin 1 enhances neovascularization and reduces ventricular remodeling during chronic myocardial infarction: a study using thioredoxin 1 transgenic mice. J Mol Cell Cardiol 50:239-47
Samuel, Samson Mathews; Thirunavukkarasu, Mahesh; Penumathsa, Suresh Varma et al. (2010) Thioredoxin-1 gene therapy enhances angiogenic signaling and reduces ventricular remodeling in infarcted myocardium of diabetic rats. Circulation 121:1244-55
Samuel, Samson Mathews; Akita, Yuzo; Paul, Debayon et al. (2010) Coadministration of adenoviral vascular endothelial growth factor and angiopoietin-1 enhances vascularization and reduces ventricular remodeling in the infarcted myocardium of type 1 diabetic rats. Diabetes 59:51-60
Penumathsa, Suresh Varma; Maulik, Nilanjana (2009) Resveratrol: a promising agent in promoting cardioprotection against coronary heart disease. Can J Physiol Pharmacol 87:275-86
Vidavalur, Ramesh; Penumathsa, Suresh Varma; Thirunavukkarasu, Mahesh et al. (2009) Sildenafil augments early protective transcriptional changes after ischemia in mouse myocardium. Gene 430:30-7
Koneru, Srikanth; Penumathsa, Suresh V; Thirunavukkarasu, Mahesh et al. (2009) Thioredoxin-1 gene delivery induces heme oxygenase-1 mediated myocardial preservation after chronic infarction in hypertensive rats. Am J Hypertens 22:183-90
Brown, Lindsay; Kroon, Paul A; Das, Dipak K et al. (2009) The biological responses to resveratrol and other polyphenols from alcoholic beverages. Alcohol Clin Exp Res 33:1513-23

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