The long-term goal of this project is to understand the fundamental molecular mechanisms of cardioprotection Our central hypothesis is that inducible nitric oxide synthase (iNOS) and heme oxygenase-1 (HO-1) protect the heart from ischemia-reperfusion (I-R)injury by partially inhibiting mitochondrial electron transport, which decreases the generation of free radicals and prevents mitochondrial permeability transition (MPT). We propose that these changes prevent ischemic cell death and are responsible for the cardioprotective effects of the late phase of preconditioning (PC). We will use electron paramagnetic resonance measurements to quantify the generation of oxygen-derived free radicals and nitric oxide and determine whether free radicals generation and oxidative stress are attenuated in preconditioned hearts subjected to I-R (Aim 1). To test the antioxidant role of iNOS and HO-1, we will measure free radical generation and oxidative stress in hearts transduced with recombinant adeno-associated virus (rAAV) carrying the iNOS or HO-1 gene. Conversely, we will determine whether I-R-induced oxidative stress and radical generation are exacerbated in the hearts of iNOS or HO-1 null mice (Aim 2). To examine whether the cardioprotective effects of late PC are derived from inhibition of MPT, we will measure permeability transition and the activity of respiratory complexes in mitochondria isolated from naive and preconditioned hearts and test whether PC decreases I-R-induced MPT in isolated perfused hearts (Aim 3). To determine the role of iNOS and HO-1, we will examine whether inhibition or the lack of these proteins abolishes the effects of PC on MPT and conversely whether hearts of mice transduced with rAAV/iNOS or rAAV/HO-1 are resistant to I-R-induced MPT. We will determine whether iNOS and HO-1 prevent mitochondrial injury by associating with the mitochondria and whether localization of these proteins to the mitochondria (by using mitochondria-specific leader sequence) is sufficient to confer cardioprotection (Aim 4).

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL078825-02
Application #
7312617
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
2
Fiscal Year
2006
Total Cost
$358,263
Indirect Cost
Name
University of Louisville
Department
Type
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Hindi, Sajedah M; Sato, Shuichi; Xiong, Guangyan et al. (2018) TAK1 regulates skeletal muscle mass and mitochondrial function. JCI Insight 3:
Mehra, Parul; Guo, Yiru; Nong, Yibing et al. (2018) Cardiac mesenchymal cells from diabetic mice are ineffective for cell therapy-mediated myocardial repair. Basic Res Cardiol 113:46
Baba, Shahid P; Zhang, Deqing; Singh, Mahavir et al. (2018) Deficiency of aldose reductase exacerbates early pressure overload-induced cardiac dysfunction and autophagy in mice. J Mol Cell Cardiol 118:183-192
Fulghum, Kyle; Hill, Bradford G (2018) Metabolic Mechanisms of Exercise-Induced Cardiac Remodeling. Front Cardiovasc Med 5:127
Hosen, Mohammed Rabiul; Militello, Giuseppe; Weirick, Tyler et al. (2018) Airn Regulates Igf2bp2 Translation in Cardiomyocytes. Circ Res 122:1347-1353
Dassanayaka, Sujith; Zheng, Yuting; Gibb, Andrew A et al. (2018) Cardiac-specific overexpression of aldehyde dehydrogenase 2 exacerbates cardiac remodeling in response to pressure overload. Redox Biol 17:440-449
Osuma, Edie A; Riggs, Daniel W; Gibb, Andrew A et al. (2018) High throughput measurement of metabolism in planarians reveals activation of glycolysis during regeneration. Regeneration (Oxf) 5:78-86
Lindsey, Merry L; Bolli, Roberto; Canty Jr, John M et al. (2018) Guidelines for experimental models of myocardial ischemia and infarction. Am J Physiol Heart Circ Physiol 314:H812-H838
Uchida, Shizuka; Jones, Steven P (2018) RNA Editing: Unexplored Opportunities in the Cardiovascular System. Circ Res 122:399-401
Wysoczynski, Marcin; Khan, Abdur; Bolli, Roberto (2018) New Paradigms in Cell Therapy: Repeated Dosing, Intravenous Delivery, Immunomodulatory Actions, and New Cell Types. Circ Res 123:138-158

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