Endogenous factors generated from myocardial endothelium are released into the circulation during and following ischemia. Factors such as nitric oxide and prostacyclin function as vasodilators while endothelin and angiotensin II are potent vasoconstrictors. Inhibition of angiotensin II formation by angiotensin converting enzyme (ACE) inhibition and/or AT1 receptor antagonism has been found to be cardioprotective. During the current grant funding, our laboratory demonstrated that available ACE AT1 receptor blockers only partially inhibit the formation of angiotensin II, because angiotensin II car be formed by more than a single pathway. We also documented that AT1 receptor blockers function by two ways: one by blocking AT1 receptors, and the other by increasing cardioprotective bradykinin formation. We plan to expand these important findings by examining 1) whether angiotensin II about formation can be blocked by AT1 antisense therapy, and if so, how such intervention would manipulate myocardial preservation; ii) whether angiotensin II antagonism leads to the formation of other intercellular mediators such as nitric oxide and prostaglandins, and if so, their contribution to cardioprotection; iii) whether detrimental compotents such as inflammatory adhesion molecules and arachidonic acid are formed by angiotensin II due to its incomplete inhibition by ACE/AT1 receptor antagonism; and finally, iv) if angiotensin II by itself provides cardioprotection by preconditioning the heart. Myocardial preconditioning with angiotensin II has recently been documented; however, the mechanism of action remains unknown. The grant proposes to examine as yet unknown intracellula signaling pathways for angiotensin II during ischemia and reperfusion. This will include phospholipase signaling, protein kinase C, and newly discovered JAK/STAT pathway. The approach will consist of a combination of molecular and cellular biological techniques, genetically engineered animals and gene therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL022559-22
Application #
6726065
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Liang, Isabella Y
Project Start
1979-08-01
Project End
2005-03-31
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
22
Fiscal Year
2004
Total Cost
$324,900
Indirect Cost
Name
University of Connecticut
Department
Surgery
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
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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