Natural compounds regulate the PI3K/Akt/GSK3β pathway in myocardial ischemia-reperfusion injury

The PI3K/Akt/GSK3β pathway is crucial in regulating cardiomyocyte growth and survival. It has been shown that activation of this pathway alleviates the negative impact of ischemia-reperfusion. Glycogen synthase kinase-3 (GSK3β) induces apoptosis through stimulation of transcription factors, and its phosphorylation has been suggested as a new therapeutic target for myocardial ischemia-reperfusion injury (MIRI). GSK3β regulatory role is mediated by the reperfusion injury salvage kinase (RISK) pathway, and its inhibition by Akt activation blocks mitochondrial permeability transition pore (mPTP) opening and enhances myocardial survival. The present article discusses the involvement of the PI3K/Akt/GSK3β pathway in cardioprotective effects of natural products against MIRI.Abbreviations: Akt: protein kinase B; AMPK: AMP-activated protein kinase; ATP: adenosine triphosphate; Bad: bcl2-associated agonist of cell death; Bax: bcl2-associated x protein; Bcl-2: B-cell lymphoma 2; CK-MB: Creatine kinase-MB; CRP: C-reactive-protein; cTnI: cardiac troponin I; EGCG: Epigallocatechin-3-gallate; Enos: endothelial nitric oxide synthase; ER: endoplasmic reticulum; ERK ½: extracellular signal‑regulated protein kinase ½; GSK3β: glycogen synthase kinase-3; GSRd: Ginsenoside Rd; GSH: glutathione; GSSG: glutathione disulfide; HO-1: heme oxygenase-1; HR: hypoxia/reoxygenation; HSYA: Hydroxysafflor Yellow A; ICAM-1: Intercellular Adhesion Molecule 1; IKK-b: IκB kinase; IL: interleukin; IPoC: Ischemic postconditioning; IRI: ischemia-reperfusion injury; JNK: c-Jun N-terminal kinase; Keap1: kelch-like ECH-associated protein- 1; LDH: lactate dehydrogenase; LVEDP: left ventricular end diastolic pressure; LVP: left ventricle pressure; LVSP: left ventricular systolic pressure; MAPK: mitogen-activated protein kinase; MDA: malondialdehyde; MIRI: myocardial ischemia-reperfusion injury; MnSOD: manganese superoxide dismutase; mPTP: mitochondrial permeability transition pore; mtHKII: mitochondria-bound hexokinase II; Nrf-1: nuclear respiratory factor 1; Nrf2: nuclear factor erythroid 2-related factor; NO: nitric oxide; PGC-1α: peroxisome proliferator‑activated receptor γ coactivator‑1α; PI3K: phosphoinositide 3-kinases; RISK: reperfusion injury salvage kinase; ROS: reactive oxygen species; RSV: Resveratrol; SOD: superoxide dismutase; TFAM: transcription factor A mitochondrial; TNF-α: tumor necrosis factor-alpha; VEGF-B: vascular endothelial growth factor B.