| First Author | Abdel Malik R | Year | 2017 |
| Journal | Circ Res | Volume | 120 |
| Issue | 1 | Pages | 99-109 |
| PubMed ID | 27777247 | Mgi Jnum | J:262008 |
| Mgi Id | MGI:6156731 | Doi | 10.1161/CIRCRESAHA.116.309937 |
| Citation | Abdel Malik R, et al. (2017) AMP-Activated Protein Kinase alpha2 in Neutrophils Regulates Vascular Repair via Hypoxia-Inducible Factor-1alpha and a Network of Proteins Affecting Metabolism and Apoptosis. Circ Res 120(1):99-109 |
| abstractText | RATIONALE: The AMP-activated protein kinase (AMPK) is stimulated by hypoxia, and although the AMPKalpha1 catalytic subunit has been implicated in angiogenesis, little is known about the role played by the AMPKalpha2 subunit in vascular repair. OBJECTIVE: To determine the role of the AMPKalpha2 subunit in vascular repair. METHODS AND RESULTS: Recovery of blood flow after femoral artery ligation was impaired (>80%) in AMPKalpha2(-/-) versus wild-type mice, a phenotype reproduced in mice lacking AMPKalpha2 in myeloid cells (AMPKalpha2(DeltaMC)). Three days after ligation, neutrophil infiltration into ischemic limbs of AMPKalpha2(DeltaMC) mice was lower than that in wild-type mice despite being higher after 24 hours. Neutrophil survival in ischemic tissue is required to attract monocytes that contribute to the angiogenic response. Indeed, apoptosis was increased in hypoxic neutrophils from AMPKalpha2(DeltaMC) mice, fewer monocytes were recruited, and gene array analysis revealed attenuated expression of proangiogenic proteins in ischemic AMPKalpha2(DeltaMC) hindlimbs. Many angiogenic growth factors are regulated by hypoxia-inducible factor, and hypoxia-inducible factor-1alpha induction was attenuated in AMPKalpha2-deficient cells and accompanied by its enhanced hydroxylation. Also, fewer proteins were regulated by hypoxia in neutrophils from AMPKalpha2(DeltaMC) mice. Mechanistically, isocitrate dehydrogenase expression and the production of alpha-ketoglutarate, which negatively regulate hypoxia-inducible factor-1alpha stability, were attenuated in neutrophils from wild-type mice but remained elevated in cells from AMPKalpha2(DeltaMC) mice. CONCLUSIONS: AMPKalpha2 regulates alpha-ketoglutarate generation, hypoxia-inducible factor-1alpha stability, and neutrophil survival, which in turn determine further myeloid cell recruitment and repair potential. The activation of AMPKalpha2 in neutrophils is a decisive event in the initiation of vascular repair after ischemia. |
