Abstract 17399: Glutathione-S-Transferase P Regulates Neovascularization in the Remodeling Heart via Effects on Endothelial Progenitor Cells and Reparative Monocytes

Abstract

Glutathione- S -transferase P (GSTP) modulates c-Jun N-terminal kinase (JNK) activation and the proliferation of bone marrow (BM) myeloid progenitors; however, its effects on endothelial progenitor cells (EPCs) and neovascularization are unknown. Hypothesis: GSTP promotes EPC function in a JNK-dependent manner, thereby supporting neovascularization in heart failure (HF). GSTP-/- mice exhibited significantly (p<0.01 vs. wild type [WT]) reduced circulating and BM EPCs, increased pro-inflammatory F4/80 + CD11b + Gr-1 hi monocytes, diminished BM EPC function (proliferation, migration, and vascular tube formation), and increased BM JNK phosphorylation. These effects were reversed upon treatment with the JNK inhibitor SP600125. HF was induced by left coronary ligation in WT and GSTP-/- mice (sham control). GSTP-/- HF mice exhibited (p<0.05 vs. WT HF): 1) fewer circulating and BM EPCs and increased pro-inflammatory monocytes; 2) exaggerated left ventricular (LV) remodeling and inflammation; and 3) reduced myocardial capillary density. Next, chimeric mice were generated via BM ablation in WT mice and reconstitution with either GSTP-/- (GSTP-/-c) or WT (WTc) BM. GSTP-/-c and WTc mice underwent coronary ligation or sham operation (n = 8-15/group). As compared with WTc HF, GSTP-/-c HF hearts had significant (p < 0.01): 1) exaggeration of LV remodeling and dysfunction; 2) increases in remote zone fibrosis; 3) reductions in capillary density and VEGF-A, -B, and -C gene expression; and 4) augmentation of interleukin (IL)-1β and IL-6 expression. GSTP-/-c mice also exhibited (p < 0.01 vs. WTc mice) increased BM JNK activation, reduced circulating EPCs, increased pro-inflammatory CD11b + Ly6C hi monocytes, but comparable Ly6C low monocytes at baseline. Moreover, at 3 and 7 d post-ligation, GSTP-/-c HF mice had fewer circulating EPCs and reparative Ly6C low monocytes, but significantly higher Ly6C hi monocytes. Conclusion: GSTP promotes EPC function and reparative monocyte mobilization, and suppresses inflammation, thereby improving angiogenic gene expression, neovascularization and LV remodeling after infarction. Hence, human GSTP polymorphisms, which are frequent, may impact cardiac reparative capacity in patients with myocardial infarction.