Neovascularization, the natural physiological process of formation of new blood vessels, is extremely important to ameliorate the function of the heart that undergoes ischemic stress. This process is potentially important for the treatment of ischemic heart and limb ischemia which includes formation of capillaries (angiogenesis) and collateral arteries. We demonstrated that ischemic preconditioning (IP) of the heart can trigger angiogenesis. Reactive oxygen species (ROS) derived from gp91phox (Nox2)-containing NAD(P)H oxidase is found to be involved in angiogenic process which involves vascular endothelial growth factor (VEGF) signaling. The role of gp91phox-derived ROS in neovascularization in response to tissue ischemia is unknown. Again to determine this redox signaling we will examine the involvement of principal redox regulated genes, thioredoxin and glutaredoxin in the IP hearts. Discerning the myriad pathways that are possibly associated with this vascular growth process is therefore of utmost importance to develop targeted drugs and bring the therapy from bench to bedside. Previous studies, including ours, also have shown that transient ischemia upregulates VEGF protein in cardiac tissues. Thus, this study will attempt to address an important clinical issue by identifying potential candidates of VEGF signaling in several gene knockout animals such as Flk-1+/-, Flt-1+/-, gp-91 phox-/-, HO-1+/+, Trx-1+/+, Grx1+/+, Grx1-/-. This study will utilize a broad multidisciplinary approach that will combine various techniques, including latest molecular biology techniques, physiology and gene targeting.
Aim 1. Activation and molecular mechanism of the GSK-3beta phosphorylation and beta-catenin translocation followed by pro-angiogenic molecule VEGF expression will be investigated.
Aim 2. Genetically-engineered mice will be used such as MK2-/- to identify down stream target candidates of VEGF signaling through its receptors in IP as well as ischemic reperfused myocardium in vivo Aim 3. ROS mediated stress plays significant role in VEGF induced angiogenesis through Trx and Grx protein.
Aim 4. To gain insights into the mechanisms and to identify candidate genes involved in VEGF- NAD(P)H oxidase signaling in gp91phox-/- homozygous mice we will use Affymetrix Gene chip Analysis. This proposal will provide and will identify important new insights into the cellular and molecular mechanisms of the cardioprotection provided by VEGF signaling through important candidate genes.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL085804-05
Application #
7848062
Study Section
Special Emphasis Panel (ZRG1-CVS-B (02))
Program Officer
Schwartz, Lisa
Project Start
2006-06-15
Project End
2013-05-31
Budget Start
2010-06-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$359,270
Indirect Cost
Name
University of Connecticut
Department
Surgery
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Oriowo, Babatunde; Thirunavukkarasu, Mahesh; Selvaraju, Vaithinathan et al. (2014) Targeted gene deletion of prolyl hydroxylase domain protein 3 triggers angiogenesis and preserves cardiac function by stabilizing hypoxia inducible factor 1 alpha following myocardial infarction. Curr Pharm Des 20:1305-10
Selvaraju, Vaithinathan; Parinandi, Narasimham L; Adluri, Ram Sudheer et al. (2014) Molecular mechanisms of action and therapeutic uses of pharmacological inhibitors of HIF-prolyl 4-hydroxylases for treatment of ischemic diseases. Antioxid Redox Signal 20:2631-65
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
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
Adluri, Ram Sudheer; Thirunavukkarasu, Mahesh; Dunna, Nageswara Rao et al. (2011) Disruption of hypoxia-inducible transcription factor-prolyl hydroxylase domain-1 (PHD-1-/-) attenuates ex vivo myocardial ischemia/reperfusion injury through hypoxia-inducible factor-1ýý transcription factor and its target genes in mice. Antioxid Redox Signal 15:1789-97
Penumathsa, Suresh Varma; Maulik, Nilanjana (2009) Resveratrol: a promising agent in promoting cardioprotection against coronary heart disease. Can J Physiol Pharmacol 87:275-86
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
Thirunavukkarasu, Mahesh; Han, Zhihua; Zhan, Lijun et al. (2008) Adeno-sh-beta-catenin abolishes ischemic preconditioning-mediated cardioprotection by downregulation of its target genes VEGF, Bcl-2, and survivin in ischemic rat myocardium. Antioxid Redox Signal 10:1475-84
Koneru, Srikanth; Varma Penumathsa, Suresh; Thirunavukkarasu, Mahesh et al. (2008) Sildenafil-mediated neovascularization and protection against myocardial ischaemia reperfusion injury in rats: role of VEGF/angiopoietin-1. J Cell Mol Med 12:2651-64

Showing the most recent 10 out of 25 publications