PI3K/Akt and HIF‑1 Signaling Pathway in Hypoxia‑ischemia (Review)

Overview

Journal Mol Med Rep

Specialty Molecular Biology

Date 2018 Aug 15

PMID 30106145

Citations 195

Authors

Zhen Zhang

Li Yao

Jinhua Yang

Zhenkang Wang

Gang Du

Affiliations

Soon will be listed here.

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.

Citing Articles

Oral SARS-CoV-2 Infection and Risk for Long Covid.

Schwartz J, Capistrano K, Hussein H, Hafedi A, Shukla D, Naqvi A Rev Med Virol. 2025; 35(2):e70029.

PMID: 40074704 PMC: 11903386. DOI: 10.1002/rmv.70029.

Acupuncture Improves Chronic Cerebral Ischemia by Inhibiting the CKLF1/HIF-1α/VEGF/Notch1 Signaling Pathway.

Guo J, Wang G, Liu T, Zhang J, Li Q, Zhu Y CNS Neurosci Ther. 2025; 31(3):e70246.

PMID: 40019048 PMC: 11868988. DOI: 10.1111/cns.70246.

Molecular Insights into Ischemia-Reperfusion Injury in Coronary Artery Disease: Mechanisms and Therapeutic Implications: A Comprehensive Review.

Ghanta S, Kattamuri L, Odueke A, Mehta J Antioxidants (Basel). 2025; 14(2).

PMID: 40002399 PMC: 11851988. DOI: 10.3390/antiox14020213.

Hypoxia Regulates the Proliferation and Apoptosis of Coronary Artery Smooth Muscle Cells Through HIF-1α Mediated Autophagy in Yak.

Yang S, Cui Y, Ma R, Yu S, Zhang H, Zhao P Biomolecules. 2025; 15(2).

PMID: 40001559 PMC: 11853270. DOI: 10.3390/biom15020256.

Vitamin D Receptor Regulates Oxidative Stress and Apoptosis Via the HIF-1α/HO-1 Pathway in Cardiomyocytes.

Li Q, Tong Y, Guo J, Liang X, Shao H, Yang L Cell Biochem Biophys. 2025; .

PMID: 39934512 DOI: 10.1007/s12013-025-01681-x.

References

Semenza G . Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning. Biochim Biophys Acta. 2010; 1813(7):1263-8. PMC: 3010308. DOI: 10.1016/j.bbamcr.2010.08.006. View

He Z, Opland D, Way K, Ueki K, Bodyak N, Kang P . Regulation of vascular endothelial growth factor expression and vascularization in the myocardium by insulin receptor and PI3K/Akt pathways in insulin resistance and ischemia. Arterioscler Thromb Vasc Biol. 2006; 26(4):787-93. DOI: 10.1161/01.ATV.0000209500.15801.4e. View

Kido M, Du L, Sullivan C, Li X, Deutsch R, Jamieson S . Hypoxia-inducible factor 1-alpha reduces infarction and attenuates progression of cardiac dysfunction after myocardial infarction in the mouse. J Am Coll Cardiol. 2005; 46(11):2116-24. DOI: 10.1016/j.jacc.2005.08.045. View

Bai W, Xing Y, Wang B, Lu X, Wang Y, Sun Y . Tongxinluo Improves Cardiac Function and Ameliorates Ventricular Remodeling in Mice Model of Myocardial Infarction through Enhancing Angiogenesis. Evid Based Complement Alternat Med. 2013; 2013:813247. PMC: 3771470. DOI: 10.1155/2013/813247. View

Han J, Yu K, He M . [Effects of puerarin on the neurocyte apoptosis and p-Akt (Ser473) expressions in rats with cerebral ischemia/reperfusion injury]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2012; 32(8):1069-72. View

Xiao Y, Peng H, Hong C, Chen Z, Deng X, Wang A . PDGF Promotes the Warburg Effect in Pulmonary Arterial Smooth Muscle Cells via Activation of the PI3K/AKT/mTOR/HIF-1α Signaling Pathway. Cell Physiol Biochem. 2017; 42(4):1603-1613. DOI: 10.1159/000479401. View

Wang Z, Si L . Hypoxia-inducible factor-1α and vascular endothelial growth factor in the cardioprotective effects of intermittent hypoxia in rats. Ups J Med Sci. 2013; 118(2):65-74. PMC: 3633332. DOI: 10.3109/03009734.2013.766914. View

Helton R, Cui J, Scheel J, Ellison J, Ames C, Gibson C . Brain-specific knock-out of hypoxia-inducible factor-1alpha reduces rather than increases hypoxic-ischemic damage. J Neurosci. 2005; 25(16):4099-107. PMC: 6724950. DOI: 10.1523/JNEUROSCI.4555-04.2005. View

Minet E, Michel G, Remacle J, Michiels C . Role of HIF-1 as a transcription factor involved in embryonic development, cancer progression and apoptosis (review). Int J Mol Med. 2000; 5(3):253-9. DOI: 10.3892/ijmm.5.3.253. View

10.

Kunze R, Zhou W, Veltkamp R, Wielockx B, Breier G, Marti H . Neuron-specific prolyl-4-hydroxylase domain 2 knockout reduces brain injury after transient cerebral ischemia. Stroke. 2012; 43(10):2748-56. DOI: 10.1161/STROKEAHA.112.669598. View

11.

Liu B, Han B, Liu F . Neuroprotective effect of pAkt and HIF-1 α on ischemia rats. Asian Pac J Trop Med. 2014; 7(3):221-5. DOI: 10.1016/S1995-7645(14)60025-0. View

12.

Wang Z, Zhang H, Xu X, Shi H, Yu X, Wang X . bFGF inhibits ER stress induced by ischemic oxidative injury via activation of the PI3K/Akt and ERK1/2 pathways. Toxicol Lett. 2012; 212(2):137-46. DOI: 10.1016/j.toxlet.2012.05.006. View

13.

Hamrick S, McQuillen P, Jiang X, Mu D, Madan A, Ferriero D . A role for hypoxia-inducible factor-1alpha in desferoxamine neuroprotection. Neurosci Lett. 2005; 379(2):96-100. DOI: 10.1016/j.neulet.2004.12.080. View

14.

Maxwell P, Pugh C, Ratcliffe P . Activation of the HIF pathway in cancer. Curr Opin Genet Dev. 2001; 11(3):293-9. DOI: 10.1016/s0959-437x(00)00193-3. View

15.

Movsas T, Weiner R, Greenberg M, Holtzman D, Galindo R . Pretreatment with Human Chorionic Gonadotropin Protects the Neonatal Brain against the Effects of Hypoxic-Ischemic Injury. Front Pediatr. 2017; 5:232. PMC: 5675846. DOI: 10.3389/fped.2017.00232. View

16.

Semenza G . Hypoxia-inducible factors in physiology and medicine. Cell. 2012; 148(3):399-408. PMC: 3437543. DOI: 10.1016/j.cell.2012.01.021. View

17.

Kim J, Tchernyshyov I, Semenza G, Dang C . HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006; 3(3):177-85. DOI: 10.1016/j.cmet.2006.02.002. View

18.

Liu M, Li G, Peng L, Qu S, Zhang Y, Peng J . PI3K/Akt/FoxO3a signaling mediates cardioprotection of FGF-2 against hydrogen peroxide-induced apoptosis in H9c2 cells. Mol Cell Biochem. 2016; 414(1-2):57-66. DOI: 10.1007/s11010-016-2658-5. View

19.

Dang C . Links between metabolism and cancer. Genes Dev. 2012; 26(9):877-90. PMC: 3347786. DOI: 10.1101/gad.189365.112. View

20.

Khan M, Varadharaj S, Ganesan L, Shobha J, Naidu M, Parinandi N . C-phycocyanin protects against ischemia-reperfusion injury of heart through involvement of p38 MAPK and ERK signaling. Am J Physiol Heart Circ Physiol. 2005; 290(5):H2136-45. DOI: 10.1152/ajpheart.01072.2005. View