Although oxidative stress is a hallmark of heart failure (HF), clinical trials with antioxidants targeting first generation reactive oxygen species (ROS) such as O2/ and H2O2 have not yielded compelling benefits. However, ROS also generate secondary intermediates derived from lipid peroxidation, including peroxides and aldehydes that amplify oxidative injury. Glutathione S-transferases (GSTs) metabolize aldehydes by catalyzing their conjugation with glutathione (GSH). Select GST isoforms also have important non-catalytic functions such as physical interactions with c-Jun N-terminal kinase (JNK) that are modulated by oxidative stress. Although GSTs play a vital role in oxidative stress responses, how GSTs impact HF is unknown. Our goal is to define the functional role of GSTP, most abundant cardiac GST isoform, in HF. Our preliminary studies indicate that GSTP is downregulated in HF, and that GSTP deficiency worsens cardiac remodeling, augments protein- aldehyde adducts, depresses circulating endothelial progenitor cells (EPCs), and impairs neovascularization. Our central hypothesis, therefore, is that GSTP is a critical cardioprotective protein in post-infarction HF that ameliorates remodeling and promotes cardiac repair. To test this hypothesis, we will perform three Specific Aims.
In Aim 1, we will define the role of GSTP, and the human GSTP variants hGSTP1*A and hGSTP1*C, in HF by examining post-infarction LV remodeling in wild-type (WT), GSTP-/-, and cardiac-specific hGSTP1*A and hGSTP1*C transgenic (Tg) mice. We will evaluate apoptosis, fibrosis, and inflammation together with glutathione levels, protein-adducted aldehydes, and JNK activation in the heart.
In Aim 2, we will determine the metabolic contribution of GSTP to the detoxification of lipid peroxidation products in the failing heart. In isolated, perfused sham-operated and failing hearts from WT, GSTP-/- and hGSTP Tg mice, using isotope labeling and mass spectrometry, we will characterize the metabolism and detoxification of unsaturated aldehydes. In tissue homogenates, we will also determine GSTP-related peroxidase activity and levels of aldehydes and lipid peroxides.
In Aim 3, we will delineate the cardiac and bone marrow (BM)-related effects by which GTSP modulates neovascularization in the failing heart. We will first determine EPC and BM progenitor cell function in WT and GSTP -/- mice, both with and without concomitant JNK inhibition. Next, we will define how GSTP ablation and hGSTP overexpression affect neovascularization and angiogenic gene expression in the sham and failing hearts from Aim 1. Lastly, we will evaluate post-infarction remodeling, inflammation, EPC mobilization, and neovascularization in chimeric mice: WT mice with GSTP-/- BM and GSTP-/- mice with WT BM. These studies will establish the role of myocardium-localized versus BM-localized GSTP in the process of remodeling, neovascularization, and inflammation in the failing heart. Collectively, this work will establish a novel paradigm of GSTP as an essential antioxidant, anti-inflammatory, and pro-angiogenic protein in HF. This model can have important diagnostic and therapeutic implications for HF patients with regard to oxidant injury.

Public Health Relevance

These studies will establish glutathione S-transferase P (GSTP) as a critical antioxidant and tissue reparative protein in heart failure and identify new determinants of oxidative injury. Hence, the results can help design new, non-classical antioxidant and regenerative therapies in heart failure. We will also evaluate the cardioprotective potency of human GSTP variants in the failing heart;important differences between GSTP variants can establish a genetic basis for variability of antioxidant responses in the heart and provide a novel biomarker for the progression of heart failure.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL099014-02
Application #
8013061
Study Section
Myocardial Ischemia and Metabolism Study Section (MIM)
Program Officer
Liang, Isabella Y
Project Start
2010-02-01
Project End
2011-09-30
Budget Start
2011-02-01
Budget End
2011-09-30
Support Year
2
Fiscal Year
2011
Total Cost
$372,500
Indirect Cost
Name
University of Louisville
Department
Type
Schools of Medicine
DUNS #
057588857
City
Louisville
State
KY
Country
United States
Zip Code
40292
Kingery, Justin R; Hamid, Tariq; Lewis, Robert K et al. (2017) Leukocyte iNOS is required for inflammation and pathological remodeling in ischemic heart failure. Basic Res Cardiol 112:19
Hamid, Tariq; Xu, Yuanyuan; Ismahil, Mohamed Ameen et al. (2016) TNF receptor signaling inhibits cardiomyogenic differentiation of cardiac stem cells and promotes a neuroadrenergic-like fate. Am J Physiol Heart Circ Physiol 311:H1189-H1201
Conklin, Daniel J; Guo, Yiru; Jagatheesan, Ganapathy et al. (2015) Genetic Deficiency of Glutathione S-Transferase P Increases Myocardial Sensitivity to Ischemia-Reperfusion Injury. Circ Res 117:437-49
Ismahil, Mohamed Ameen; Hamid, Tariq; Bansal, Shyam S et al. (2014) Remodeling of the mononuclear phagocyte network underlies chronic inflammation and disease progression in heart failure: critical importance of the cardiosplenic axis. Circ Res 114:266-82
Prabhu, Sumanth D (2014) It takes two to tango: monocyte and macrophage duality in the infarcted heart. Circ Res 114:1558-60
Facundo, Heberty T; Brainard, Robert E; Watson, Lewis J et al. (2012) O-GlcNAc signaling is essential for NFAT-mediated transcriptional reprogramming during cardiomyocyte hypertrophy. Am J Physiol Heart Circ Physiol 302:H2122-30
Tan, Yi; Li, Xiaokun; Prabhu, Sumanth D et al. (2012) Angiotensin II plays a critical role in alcohol-induced cardiac nitrative damage, cell death, remodeling, and cardiomyopathy in a protein kinase C/nicotinamide adenine dinucleotide phosphate oxidase-dependent manner. J Am Coll Cardiol 59:1477-86
Rai, Shesh N; Ray, Herman E; Yuan, Xiaobin et al. (2012) Statistical Analysis of Repeated MicroRNA High-Throughput Data with Application to Human Heart Failure: A Review of Methodology. Open Access Med Stat 2012:21-31
Hamid, Tariq; Guo, Shang Z; Kingery, Justin R et al. (2011) Cardiomyocyte NF-?B p65 promotes adverse remodelling, apoptosis, and endoplasmic reticulum stress in heart failure. Cardiovasc Res 89:129-38
Ismahil, Mohamed Ameen; Hamid, Tariq; Haberzettl, Petra et al. (2011) Chronic oral exposure to the aldehyde pollutant acrolein induces dilated cardiomyopathy. Am J Physiol Heart Circ Physiol 301:H2050-60

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