Abstract 18339: Glutathione S-Transferase P (GSTP) is a Critical Cardioprotective Protein in Heart Failure That Alleviates Apoptosis, Inflammation, and Cardiac Remodeling
Heart failure (HF) is characterized by increased lipid peroxidation products (e.g., unsaturated aldehydes) that amplify oxidative injury. Glutathione S-transferases (GSTs) metabolize electrophilic aldehydes by catalyzing their conjugation with glutathione. GSTs are central to antioxidant defense; however, their role in HF is unknown. Accordingly, we hypothesized that GSTP, the most abundant cardiac GST isoform, is a critical antioxidant and anti-inflammatory protein in HF. We examined left ventricular (LV) remodeling following coronary ligation (or sham-operation) in wild-type (WT) and GSTP-/- mice (n = 8-10/group). Echocardiography revealed no baseline cardiac phenotype in GSTP-/- mice. Compared to WT sham 4 wks after surgery, WT HF hearts exhibited significant (p < 0.05): 1) LV dilatation (EDV 76 ± 33 vs 53 ± 2 μL) and systolic dysfunction (LVEF 51 ± 5 vs 67 ± 3 %); 2) hypertrophy (LV/tibia length [TL] 5.3 ± 1.0 vs 4.1 ± 0.3 mg/mm); 3) ∼30-40% downregulation of myocardial GSTP and GSTPA protein; 4) ∼4-fold increase in protein-acrolein adducts; 5) ∼3-fold increase in myocardial apoptosis by TUNEL staining; and 6) inflammatory activation as indexed by NF-κB DNA binding activity and mRNA levels of interleukin (IL)-1β and IL-6. In contrast, as compared to WT HF, GSTP-/- HF hearts had significant (p < 0.05): 1) worsening of LV dilatation (LVEDV 112 ± 51 μL), systolic dysfunction (LVEF 37 ± 5 %), and wall thinning (anterior wall thickness [AWT] 0.47 ± 0.15 vs 0.57 ± 0.11 mm), but similar degrees of LV chamber hypertrophy; 2) augmentation of protein-acrolein adducts; 3) NF-κB activation, and 4) 2-5-fold increase in IL-1β and IL-6 expression. Importantly, GSTP-/- HF hearts also exhibited a ∼2-fold increase in apoptosis over WT HF, suggesting that differences in cell loss accounted for comparable degrees of chamber hypertrophy despite differences in LV dilatation. We conclude that there is decreased capacity for metabolizing toxic aldehydes in the failing heart with downregulation of GSTP and GSTA. GSTP plays a key cardioprotective role in HF, and alleviates pathological LV remodeling, inflammation, and apoptosis in the failing heart. GSTP-mediated cardioprotection may be in part related to its detoxification of reactive lipid peroxidation-derived aldehydes.
- © 2011 by American Heart Association, Inc.