PI3K/Akt and HIF‑1 signaling pathway in hypoxia‑ischemia (Review)

Abstract

Hypoxia‑ischemia (H‑I) is frequently observed in perinatal asphyxia and other diseases. It can lead to serious cardiac injury, cerebral damage, neurological disability and mortality. Previous studies have demonstrated that the phosphatidylinositol‑3 kinase (PI3K)/protein kinase B (Akt) signaling pathway, which regulates a wide range of cellular functions, is involved in the resistance response to H‑I through the activation of proteins associated with survival and inactivation of apoptosis‑associated proteins. It can also regulate the expression of hypoxia‑induced factor‑1α (HIF‑1α). HIF‑1α can further regulate the expression of downstream proteins involved in glucose metabolism and angiogenesis, such as vascular endothelial growth factor and erythropoietin, to facilitate ischemic adaptation. Notably, HIF‑1α may also induce detrimental effects. The effects of HIF‑1 on ischemic outcomes may be dependent on the H‑I duration, animal age and species. Thus, further investigation of the PI3K/Akt signaling pathway may provide further insights of the potential targets for treating diseases accompanied by H‑I.

Figure 1.

PI3K/Akt signaling pathway in HI. Dotted arrows represent the response under normoxia, and solid arrows represent the response under HI. PI3K, phosphatidylinositol 3 kinase; Akt, protein kinase B; HI, hypoxia-ischemia; RTK, receptor tyrosine kinase; HIF, hypoxia-induced factor; PTEN, phosphatase and tensin homologue; FoxO3a, Forkhead box O3; mTOR, mammalian target of rapamycin; FRAP, FKBP-rapamycin associated protein; pVHL, von Hippel-Lindau tumor suppressor protein; P300/CBP, cyclic-adenosine monophosphate-response element-binding protein binding protein; BCL2, B-cell lymphoma 2; Bax, Bcl-2-associated X protein; eNOS, endothelial cell nitric oxide synthase.

Figure 2.

Mechanism underlying the protective effect of HIF-1 in HI. Blunt arrow represents inhibitory regulation, and pointed arrows represent stimulatory regulation. HIF1, hypoxia-induced factor 1; H-I, hypoxia-ischemia; FGF, fibroblast growth factor; VEGF, vascular endothelial growth factor; EPO, erythropoietin; GLUTs, glucose transporters; Cyt C, cytochrome C.