Abstract 19635: Glutathione-S-Transferase P Regulates Endothelial Progenitor Cell (EPC) Function in a c-Jun N-terminal kinase(JNK)-Dependent Manner and Enhances Neovascularization in Post-Infarction Heart Failure
Glutathione-S-transferase P (GSTP), via non-catalytic inhibition of JNK, modulates proliferation of bone marrow (BM) myeloid progenitors; however, its effects on EPCs are unknown. We hypothesized that GSTP supports normal EPC function via JNK suppression in BM-derived cells, and thereby promotes neovascularization in heart failure (HF). EPCs (CD34+VEGFR2+) and activated monocytes (F4/80+CD11b+) in BM and peripheral blood (PB) were determined by flow cytometry in wild type (WT) and GSTP-/- mice. Compared with WT, GSTP-/- mice exhibited significantly (p<0.01) reduced EPC number in PB (0.13±0.03 vs 0.21±0.07%) and BM (1.0±0.2 vs 1.7±0.6%), and increased activated monocytes, despite augmented numbers of CD34+CD45+ BM hematopoietic stem cells (HSCs; 6.7±0.8 vs 5.8±0.44%). PB EPCs in GSTP-/- mice were restored (p<0.05) with 5 days treatment in vivo with the specific JNK inhibitor, SP600125 (0.26±0.05% vs 0.15±0.04% before SP60025), whereas circulating activated monocytes were significantly reduced. Compared with WT, GSTP-/- BM-derived mononuclear cells cultured in endothelial growth medium for 10 d demonstrated reduced EPC colonies, less EPC migration in Transwell plates (VEGF gradient), and diminished vascular tube formation, indicating that GSTP deficiency decreased EPC differentiation from BM progenitors and EPC functional characteristics. All of these parameters were restored upon concomitant treatment with SP600125, and JNK phosphorylation, which was augmented in GSTP-/- BM, was significantly decreased by SP600125, suggesting JNK dependence of the GSTP-mediated effects on EPCs. Furthermore, EPCs, monocytes, and cardiac remodeling were examined WT and GSTP-/- mice with HF induced by left coronary ligation. As compared with WT, GSTP-/- HF mice exhibited (p<0.05): 1) fewer circulating PB EPCs and increased activated monocytes; 2) increased BM-HSCs but reduced BM EPCs; and 3) exaggerated pathological remodeling, augmented inflammation, and reduced capillary density and neovascularization in failing hearts. We conclude that GSTP promotes EPC function, mediated by inhibition of JNK in BM-derived progenitor cells, and also suppresses inflammation, and thereby imparts cardioprotective benefits in the post-infarct failing heart.
- © 2012 by American Heart Association, Inc.