Abstract

Following myocardial infarction (MI), there is a progressive myocardial remodeling characterized by left ventricular (LV) dilation, contractile dysfunction, myocyte hypertrophy and increased matrix protein formation. The proposed project will examine the molecular mechanism(s) of hypoxic preconditioning (HP)- mediated myocardial remodeling in the infarcted heart by studying cardioprotective parameters at the transcriptional and protein level. We have established the optimal hypoxic preconditioning stimulus in rat MI model (10%O2/90%NS) to initiate capillary/arteriolar formation, increased blood flow and ventricular function in the myocardium. To establish the role of such HP in potentiating the signal transduction process for ventricular remodeling we will examine (i) the expression of VEGF and its tyrosine kinase receptors VEGFR1 (Flt-1) and VEGFR2 (FIk-1), expression and activity of protein kinase C, MAP Kinases-Aim I (ii) the expression and activity of iNOS/eNOS will be determined along with the transcriptional regulation of these factors by NFkB, Stat1-Aim 2 (iii) the extent of endothelial cell (EC) survival and the extent of necrosis/apoptosis, anti-apoptotic proteins Bcl-2, survivin expression, PI-3-Kinase activity, and the extent of AKT/BAD phosphorylation -Aim 3. Our rat MI model subjected to HP before LAD occlusion has significant advantage to study the molecular mechanism of myocardial remodeling over several months. An obligatory role of FIk-1, iNOS and eNOS in VEGF mediated signaling in myocardial angiogenesis/remodeling will be established by the use of Flk1, iNOS-/- and eNOS-/- knockout mice. The endothelial cell proliferation will be studied by BrdU incorporation assay, cardiomyocyte and endothelial cell apoptosis will be studied by double antibody staining, capillary and arteriolar density will be determined by labeling endothelial and smoothe muscle cells using anti-rat CD31 and anti-smooth muscle actin respectively. The results of this study will establish whether protein kinase-C, MAP kinases, eNOS/iNOS/NO are involved in VEGF and/or receptors (FIk-1/FIt-1) mediated myocardial regulation of HP induced remodeling in rat MI model. The results will provide new information required for new therapeutic strategies to protect the heart in patients with cardiac stress or coronary heart disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL069910-02
Application #
6776943
Study Section
Cardiovascular and Renal Study Section (CVB)
Program Officer
Liang, Isabella Y
Project Start
2003-08-01
Project End
2008-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
2
Fiscal Year
2004
Total Cost
$362,500
Indirect Cost

  Institution

Name
University of Connecticut
Department
Surgery
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030

  Publications

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
Adluri, Ram Sudheer; Thirunavukkarasu, Mahesh; Zhan, Lijun et al. (2012) Glutaredoxin-1 overexpression enhances neovascularization and diminishes ventricular remodeling in chronic myocardial infarction. PLoS One 7:e34790
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
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
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
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
Mukherjee, Subhendu; Lekli, Istvan; Goswami, Shyamal et al. (2009) Freshly crushed garlic is a superior cardioprotective agent than processed garlic. J Agric Food Chem 57:7137-44

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