In hearts with volume overload, a complex sequence of compensatory events result in a continual state of extra cellular matrix (ECM) remodeling and by changes in myocyte function and eventually leads to congestive heart failure (HF). Increasing evidence suggests that reactive oxygen (ROS) and nitrogen (RNS) species, collectively termed reactive inflammatory species (RIS), and the enzymes that regulate their bioavailability are associated with contractile failure and myocardial structural damage in end-stage HF models. However, the relationship between RIS and the temporal progression of HF has not been extensively studied. Using an aortocaval fistula (ACF) model in the rat, 3 key, clinically relevant, time points in the temporal progression of volume overload have been rigorously defined in vivo: acute (2-5 days), chronic compensated (4-8 weeks), and chronic decompensated (15-21 weeks). Preliminary studies indicate increased tyrosine nitration of myofilament proteins, matrix degrading enzymes and signaling molecules during the acute phase of HF. An imbalance between RIS generating enzymes and antioxidant defenses was also observed acute stage and during the transition to decompensated HF. Moreover, we have found that RIS cause contractile dysfunction in isolated adult cardiac myocytes. This led to the hypothesis that RIS are important mediators of adverse LV remodeling and contractile dysfunction that underlie the development and progression of volume overload-induced HF.
Aim 1 will establish a link between reactive inflammatory species and the development and progression of volume overload-induced CHF. RIS will be measured using a combination of microdialysis, ESR (electron spin resonance) and standard biochemical assays. A series of pharmacological interventions and transgenic approaches (iNOS(-/-), myeloperoxidase (-/-), SOD overexpressors) will be used to manipulate RIS levels in vivo. A proteomics approach will used to identify RIS-modulated proteins.
Aim 2 will determine the mechanisms by which RIS contribute to LV remodeling in ACF-induced HF, with particular focus on ECM turnover in vivo and the regulation matrix metalloproteinase (MMP) activation by cardiac fibroblasts in vitro.
Aim 3 will use video edge microscopy, fluorescent Ca 2+ imaging and immunocytochemistry to determine whether altered susceptibility to RIS during HF progression contributes to cardiomyocyte. The proposed investigations are fundamentally important to the development of therapeutic strategies targeted to oxidant-induced injury and may have important implications in the treatment of HF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL063318-07
Application #
6951216
Study Section
Experimental Cardiovascular Sciences Study Section (ECS)
Program Officer
Massicot-Fisher, Judith
Project Start
1999-07-01
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
7
Fiscal Year
2005
Total Cost
$284,000
Indirect Cost
Name
Louisiana State University Hsc New Orleans
Department
Pharmacology
Type
Schools of Medicine
DUNS #
782627814
City
New Orleans
State
LA
Country
United States
Zip Code
70112
Guggilam, Anuradha; Hutchinson, Kirk R; West, T Aaron et al. (2013) In vivo and in vitro cardiac responses to beta-adrenergic stimulation in volume-overload heart failure. J Mol Cell Cardiol 57:47-58
Trask, Aaron J; Katz, Paige S; Kelly, Amy P et al. (2012) Dynamic micro- and macrovascular remodeling in coronary circulation of obese Ossabaw pigs with metabolic syndrome. J Appl Physiol (1985) 113:1128-40
Katz, Paige S; Trask, Aaron J; Souza-Smith, Flavia M et al. (2011) Coronary arterioles in type 2 diabetic (db/db) mice undergo a distinct pattern of remodeling associated with decreased vessel stiffness. Basic Res Cardiol 106:1123-34
Hutchinson, Kirk R; Guggilam, Anuradha; Cismowski, Mary J et al. (2011) Temporal pattern of left ventricular structural and functional remodeling following reversal of volume overload heart failure. J Appl Physiol (1985) 111:1778-88
Lord, Kevin C; Shenouda, Sylvia K; McIlwain, Elizabeth et al. (2010) Oxidative stress contributes to methamphetamine-induced left ventricular dysfunction. Cardiovasc Res 87:111-8
Shenouda, Sylvia K; Varner, Kurt J; Carvalho, Felix et al. (2009) Metabolites of MDMA induce oxidative stress and contractile dysfunction in adult rat left ventricular myocytes. Cardiovasc Toxicol 9:30-8
Shenouda, Sylvia K; Lord, Kevin C; McIlwain, Elizabeth et al. (2008) Ecstasy produces left ventricular dysfunction and oxidative stress in rats. Cardiovasc Res 79:662-70
Ryan, Thomas D; Rothstein, Emily C; Aban, Inmaculada et al. (2007) Left ventricular eccentric remodeling and matrix loss are mediated by bradykinin and precede cardiomyocyte elongation in rats with volume overload. J Am Coll Cardiol 49:811-21
Rocic, Petra; Jo, Hanjoong; Lucchesi, Pamela A (2003) A role for PYK2 in ANG II-dependent regulation of the PHAS-1-eIF4E complex by multiple signaling cascades in vascular smooth muscle. Am J Physiol Cell Physiol 285:C1437-44
Rothstein, Emily C; Byron, Kenneth L; Reed, Ryan E et al. (2002) H(2)O(2)-induced Ca(2+) overload in NRVM involves ERK1/2 MAP kinases: role for an NHE-1-dependent pathway. Am J Physiol Heart Circ Physiol 283:H598-605

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