After myocardial infarction (MI) there is progressive remodeling of the remaining, viable left ventricular (LV) myocardium resulting in chamber dilation, pump dysfunction and clinical heart failure. LV remodeling is associated with profound molecular and cellular changes in myocytes including abnormal geometry, apoptosis and reversion to a fetal contractile phenotype. In vitro, nitric oxide (NO), superoxide (O2-) and their chemical product, peroxynitrite (ONOO-) mimic many of the molecular and cellular events observed in myocardial remodeling. NO and O2- are increased in failing myocardium in association with increased expression of NOS2 and decreased SOD activity. The investigators have shown that remodeling stimuli increase levels of NO and O2- in cardiac myocytes. Their central hypothesis is that NO and O2- exert deleterious effects on LV remodeling after MI by mediating the actions of remodeling stimuli on cardiac myocytes. By genetic and pharmacological manipulation of myocardial NO and O2-levels, the investigators will assess the roles of these chemicals in causing structural and functional remodeling in a mouse model of post-MI remodeling and failure. They propose a comprehensive, multidisciplinary approach utilizing studies at the whole animal, intact organ, isolated myocyte and molecular levels.
In Aims 1 and 2, the investigators will study LV remodeling in mice that lack inducible NO synthase (NOS2) or over-express manganese superoxide dismutase.
In Aims 3 and 4, they will test whether clinically-relevant treatment strategies that reduce myocardial NO and O2-can ameliorate post-MI remodeling, and thereby improve exercise function and survival.
In Aim 5, they will use in vivo and in vitro approaches to elucidate the mechanism responsible for increased o2-levels in the mouse heart post-MI, and to evaluate potential therapeutic strategies for use in Aim 3.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL061639-03
Application #
6185076
Study Section
Special Emphasis Panel (ZHL1-CSR-F (S1))
Project Start
1998-09-30
Project End
2003-08-31
Budget Start
2000-09-30
Budget End
2001-08-31
Support Year
3
Fiscal Year
2000
Total Cost
$407,500
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Hobai, Ion A; Aziz, Kanwal; Buys, Emmanuel S et al. (2016) Distinct Myocardial Mechanisms Underlie Cardiac Dysfunction in Endotoxemic Male and Female Mice. Shock 46:713-722
Sverdlov, Aaron L; Elezaby, Aly; Behring, Jessica B et al. (2015) High fat, high sucrose diet causes cardiac mitochondrial dysfunction due in part to oxidative post-translational modification of mitochondrial complex II. J Mol Cell Cardiol 78:165-73
Calamaras, Timothy D; Lee, Charlie; Lan, Fan et al. (2015) The lipid peroxidation product 4-hydroxy-trans-2-nonenal causes protein synthesis in cardiac myocytes via activated mTORC1-p70S6K-RPS6 signaling. Free Radic Biol Med 82:137-46
Hobai, Ion A; Morse, Justin C; Siwik, Deborah A et al. (2015) Lipopolysaccharide and cytokines inhibit rat cardiomyocyte contractility in vitro. J Surg Res 193:888-901
Qin, Fuzhong; Siwik, Deborah A; Pimentel, David R et al. (2014) Cytosolic H2O2 mediates hypertrophy, apoptosis, and decreased SERCA activity in mice with chronic hemodynamic overload. Am J Physiol Heart Circ Physiol 306:H1453-63
Qin, Fuzhong; Siwik, Deborah A; Lancel, Steve et al. (2013) Hydrogen peroxide-mediated SERCA cysteine 674 oxidation contributes to impaired cardiac myocyte relaxation in senescent mouse heart. J Am Heart Assoc 2:e000184
Hobai, Ion A; Buys, Emmanuel S; Morse, Justin C et al. (2013) SERCA Cys674 sulphonylation and inhibition of L-type Ca2+ influx contribute to cardiac dysfunction in endotoxemic mice, independent of cGMP synthesis. Am J Physiol Heart Circ Physiol 305:H1189-200
Qin, Fuzhong; Siwik, Deborah A; Luptak, Ivan et al. (2012) The polyphenols resveratrol and S17834 prevent the structural and functional sequelae of diet-induced metabolic heart disease in mice. Circulation 125:1757-64, S1-6
Calamaras, Timothy D; Lee, Charlie; Lan, Fan et al. (2012) Post-translational modification of serine/threonine kinase LKB1 via Adduction of the Reactive Lipid Species 4-Hydroxy-trans-2-nonenal (HNE) at lysine residue 97 directly inhibits kinase activity. J Biol Chem 287:42400-6
Liesa, Marc; Luptak, Ivan; Qin, Fuzhong et al. (2011) Mitochondrial transporter ATP binding cassette mitochondrial erythroid is a novel gene required for cardiac recovery after ischemia/reperfusion. Circulation 124:806-13

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