Abstract 347: Glutathione-S-Transferase P Regulates Bone Marrow Derived Endothelial Progenitor Cell (EPC) Function and Neovascularization in the Infarcted Heart

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Abstract

Glutathione-S-transferase P (GSTP) modulates proliferation of bone marrow (BM) myeloid progenitors via non-catalytic inhibition of c-Jun N-terminal kinase (JNK); however, its effects on BM-derived EPCs are unknown. We hypothesized that GSTP supports EPC mobilization while suppressing inflammatory cells, thereby promoting tissue neovascularization. We generated chimeric mice using BM-ablated wild-type (WT) mice reconstituted with either GSTP-/- (GSTP-/-c) or WT (WTc) BM. GSTP-/-c and WTc mice underwent coronary ligation or sham operation (n = 8-15/group). Compared to WTc sham, 4 w after surgery, WTc HF mice exhibited significant (p < 0.05): LV dilatation, dysfunction, and fibrosis; increased mortality; and augmented circulating pro-inflammatory CD11b+Ly6Chi monocytes, but comparable circulating CD34+VEGFR2+ EPCs. In contrast, compared to WTc HF, GSTP-/-c HF hearts had significant (p < 0.01): 1) worsening of LV dilatation (LVEDV 118 ± 30 vs 88 ± 13 μL), dysfunction (LVEF 21 ± 4 vs 32 ± 9 %), wall thinning (anterior wall thickness 0.41 ± 0.06 vs 0.49 ± 0.1 mm), and LV hypertrophy (LV/tibia length 4.9 ± 0.5 vs 4.5 ± 0.6 mg/mm); 2) increased remote zone fibrosis by trichrome staining (1.3 ± 0.2 vs 0.61 ± 0.3 %); 3) reduced capillary density (476 ± 60 vs 544 ± 37 capillary/mm2) and increased capillary area (14 ± 1.1 vs 12 ± 1.2 μm2); 4) diminished gene expression of VEGF A, VEGF B, and VEGF C; 5) and increased IL-1β, IL-6 gene expression. GSTP-/-c mice also exhibited (p < 0.01) increased BM JNK activation, reduced circulating EPCs (0.18±0.07 vs 0.24±0.06%), increased CD11b+Ly6Chi monocytes (2.25±0.5 vs 1.8±0.6%), but comparable anti-inflammatory CD11b+Ly6Clow monocytes at baseline as compared with WTc mice. Moreover, at 3 and 7 d after ligation, GSTP-/-c HF mice exhibited fewer circulating EPCs and anti-inflammatory monocytes, and significantly higher pro-inflammatory monocytes as compared with WTc HF mice. We conclude that GSTP promotes EPC and reparative monocyte mobilization, thereby improving angiogenic gene expression, neovascularization and LV remodeling after myocardial infarction. This suggests that GSTP polymorphisms can impact cardiac reparative capacity in humans, and that enhancing GSTP function after infarction may yield therapeutic benefit.

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