AMP-Activated Protein Kinase [alpha]2 in Neutrophils Regulates Vascular Repair via Hypoxia-Inducible Factor-1[alpha] and a Network of Proteins Affecting Metabolism and Apoptosis.
Abdel Malik, Randa; Zippel, Nina; Fromel, Timo; Heidler, Juliana; Zukunft, Sven; Walzog, Barbara; Ansari, Nariman; Pampaloni, Francesco; Wingert, Susanne; Rieger, Michael A.; Wittig, Ilka; Fisslthaler, Beate; Fleming, Ingrid
120(1):99-109, January 6, 2017.
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Rationale: The AMP-activated protein kinase (AMPK) is stimulated by hypoxia, and although the AMPK[alpha]1 catalytic subunit has been implicated in angiogenesis, little is known about the role played by the AMPK[alpha]2 subunit in vascular repair.
Objective: To determine the role of the AMPK[alpha]2 subunit in vascular repair.
Methods and Results: Recovery of blood flow after femoral artery ligation was impaired (>80%) in AMPK[alpha]2-/- versus wild-type mice, a phenotype reproduced in mice lacking AMPK[alpha]2 in myeloid cells (AMPK[alpha]2[DELTA]MC). Three days after ligation, neutrophil infiltration into ischemic limbs of AMPK[alpha]2[DELTA]MC 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 AMPK[alpha]2[DELTA]MC mice, fewer monocytes were recruited, and gene array analysis revealed attenuated expression of proangiogenic proteins in ischemic AMPK[alpha]2[DELTA]MC hindlimbs. Many angiogenic growth factors are regulated by hypoxia-inducible factor, and hypoxia-inducible factor-1[alpha] induction was attenuated in AMPK[alpha]2-deficient cells and accompanied by its enhanced hydroxylation. Also, fewer proteins were regulated by hypoxia in neutrophils from AMPK[alpha]2[DELTA]MC mice. Mechanistically, isocitrate dehydrogenase expression and the production of [alpha]-ketoglutarate, which negatively regulate hypoxia-inducible factor-1[alpha] stability, were attenuated in neutrophils from wild-type mice but remained elevated in cells from AMPK[alpha]2[DELTA]MC mice.
Conclusions: AMPK[alpha]2 regulates [alpha]-ketoglutarate generation, hypoxia-inducible factor-1[alpha] stability, and neutrophil survival, which in turn determine further myeloid cell recruitment and repair potential. The activation of AMPK[alpha]2 in neutrophils is a decisive event in the initiation of vascular repair after ischemia.
(C) 2017 American Heart Association, Inc.