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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Myocardial Ischemia and Metabolism Study Section (MIM)
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Wong, Renee P
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University of Alabama Birmingham
Internal Medicine/Medicine
Schools of Medicine
United States
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