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

Figures & data

Figure 1. The protective mechanisms mediated through regulation of PI3K/Akt/GSK3β against myocardial ischemia-reperfusion injury. ATP, adenosine triphosphate; Bcl‐2, B-cell lymphoma 2; eNOS, endothelial nitric oxide synthase; HO-1, heme oxygenase-1; mPTP, mitochondrial permeability transition pore; NO, Nitric oxide; ROS, reactive oxygen species; SOD, superoxide dismutase; and TNF-α, tumor necrosis factor-alpha.

Table 1. Natural compounds that protect against myocardial ischemia-reperfusion injury via phosphorylation of PI3K/Akt/GSK3β.

Natural compound	Experimental model	NCs Dose/Route/Time	Findings	Reference
Syringic acid	Rats	50 mg/kg gavage for 3 days, 30-minute ischemia followed by 120-minute reperfusion	↑LVEF, LVFS, ↑p-PI3K, p-Akt, p-GSK3β, Bcl-2 ↓MI size,caspase-3 and −9, Bax	[38]
Berberine	Type 2 diabetic rats	100 mg/kg gavage for 7 days	↑p-Akt, p-GSK3β ↓MI size, arrhythmia, TG, cholesterol, MDA level	[48]
Epigallocatechin-3-gallate	Rats	10 mg/kg i.p. 5 minutes before the onset of reperfusion	↓MI size, p38, and JNK ↑p-Akt, p-GSK3β	[54]
Hydroxysafflor yellow A	H9c2 cells	1.25, 5, and 20 mM during reoxygenation for 4 hours	↓LDH, Caspase 3, oxidative stress, apoptosis ↑Mitochondrial energy metabolism	[63]
Resveratrol	Rats	10 μmol/L 15 minutes prior to the ischemia period	↑VEGF-B mRNA, Akt expression ↓CK-MB release, GSK3β expression, MI size, apoptosis, ROS generation by MnSOD up-regulation	[77]
Kaempferol	Rats	15 mmol/L for 10 min after being subjected to global ischemia for 15 minutes and reperfusion for 85 minutes	↑SOD, P-GSK3β, GSH/GSSG ratio levels. ↓MI size, caspase-3, cytoplasm cytochrome C, LDH, MDA, and TNF-α.	[81]
Safranal	Rats	0.1–0.5 ml/kg/day, i.p. for14 days, and on the 15th day, one-stage ligation of LAD for 45 minutes was performed, followed by 60-minute reperfusion	↓MI size, CK-MB, TNF-a, IKK-b/NF-κB, apoptosis ↑LV function, p-Akt, p-GSK3β, p-eNOS, myocardial antioxidant, nitrotyrosine levels.	[95]
Astragaloside IV	Rats	2.5, 5 and 10 mg/kg, intragastrical for 7 days	↓ LVEDP, LDH, CK, MI size ↑ LVSP, FS, EF ↑p-Akt, p-GSK3β	[107]
Kaempferide	Rats	0.1, 0.3 and 1 mg/kg injection 30 minutes prior to a 30-minute LAD coronary artery ligation followed by a 2 hour reperfusion	↑p-Akt, p-GSK3β, SOD ↓MI size, TNF-α, IL-6, CRP ↓MDA, ROS, caspase-3	[112]
Ginsenoside Rd	Rats Neonatal rat cardiomyocytes	50 mg/kg i.p. for 30 minutes prior to coronary IR 10 mM for 30 minutes followed by I/R treatment	↑LVEF, p-Akt, p-GSK3β, Bcl-2/Bax ratio. ↓MI size, apoptosis, CK-MB, LDH, ROS, caspase-9/3	[119]
Curcumin	Rats	100 mg/kg 20 minutes before LAD occlusion	↓MI size, p38, JNK expression ↑p-Akt/p-ERK1/2/p-GSK3β	[75]
Fisetin	Rats	20 mg/kg i.p. 1 hour before ischemia induction	↓IR injury, oxidative stress, mitochondrial dysfunction ↑p-GSK3β	[130]
Leonurine	Rats	15 mg/kg/day oral gavage following the onset of MI	↓Collagen deposition, caspase3, Bax expression, MI size, apoptosis ↑Myocardial function, p-PI3K/p-AKT/p-GSK3β, Bcl2,	[178]
Lycopene	Rats	5 mg/kg/day i.p. for 5 consecutive days before ischemia and reperfusion	↓MI size, cytochrome c, caspase‑9/3, mPTP opening, apoptosis ↑p-AKT/p-ERK1/2/p-GSK3β	[143]
Rhein	H9c2 cells	1 h incubation with 1 μg/mL rhein prior to 6 h hypoxia followed by 2 h reoxygenation	↓Apoptosis, ROS, p-P38 ↑p-AKT/p-GSK3β	[27]
Salvianolic Acid A	Rat Cardiomyocytes	12.5, 25, and 50 μg/mL salvianolic Acid A at the beginning of hypoxia and reoxygenation	↓ROS, apoptosis, caspase 3, Bax/Bcl-2 ratio, and mPTP activation ↑ p-AKT/p-GSK3β	[149]
Shikonin	H9C2 cells	10, 20 and 40 μM of shikonin 2 hours prior to HR	↑ p-AKT/p-GSK3β ↓LDH, apoptosis ↓cytochrome c release	[155]
Spinosin and6‘‑Feruloylspinosin	Rats	5 mg/kg i.p. 30 minutes before LAD ligation.	↓MI size, apoptosis ↑ p-GSK3β ↑PGC‑1α, Nrf2, HO‑ 1	[160]
Urolithin B	Sprague Dawley rats H9c2 cardiomyocytes	0.7 mg/kg UB 0, 24 and 48 h before 30 min LADA ligation followed by 120 min reperfusion 20 μM 12 h prior to 3 h hypoxia followed by 3 h reoxygenation	↓MI size, CK-MB, LDH, MDA ↑LVEF, p62 level ↓Autophagy, ROS, oxidative stress, caspase 3, apoptosis ↑Nrf2, HO-1, NQO1,GSTP, p-Akt	[175]
Urolithin A	Male adult C57BL/6 mice neonatal rat cardiomyocytes (NRCs)	1 mg/kg UA in 0.5 ml dimethylsulfoxide i.p., 24 and 1 h before 45 min ischemia followed by 24 h reperfusion. 10 μM UA at 24 and 1 h prior to 3h hypoxia followed by 3 h reoxygenation	↓MI size, apoptosis, CK-MB, LDH ↑LVFS, EF ↓ ROS, MDA content Bcl-2/Bax ratio, caspase 3 ↑SOD activity, p-Akt	[177]

Abbreviations: Bax, bcl2-associated x protein; Bcl-2, B-cell lymphoma 2; CK-MB, creatine kinase-MB; CRP, C-reactive-protein; EF, ejection fraction; eNOS, endothelial nitric oxide synthase; ERK1/2, extracellular signal‑regulated protein kinase 1/2; FS, fractional shortening; GSH, glutathione; GSSG, glutathione disulfide; GSTP1, glutathione S-transferase P1; HO‑ 1, heme oxygenase-1; IKK, IκB kinase; JNK, c-Jun N-terminal kinase; LADA, left anterior descending artery; LDH, lactate dehydrogenase; LV, left ventricular; LVEDP, left ventricular end diastolic pressure; LVEF, Left ventricular ejection fraction; LVFS, Left ventricular function measurements; LVSP, left ventricular systolic pressure; MDA, malondialdehyde; MI, myocardial infarction; mPTP, mitochondrial permeability transition pore; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; NQO1, NAD(P)H dehydrogenase [quinone] 1; Nrf2, nuclear factor erythroid 2-related factor; p-Akt, phosphorylated Ak strain transforming; PGC‑1α, peroxisome proliferator‑activated receptor γ coactivator‑1α; p-GSK3β, phosphorylated glycogen synthase kinase 3 beta; p-PI3K, phosphorylated phosphoinositide 3-kinases; ROS, reactive oxygen species; SOD, superoxide dismutase; TG, triglycerides; TNF-α, tumor necrosis factor-alpha; VEGF-B, vascular endothelial growth factor B.

Figure 2. The regulatory effects of natural compounds on the PI3K/Akt/GSK3β signaling pathway. Ischemia-reperfusion in cardiomyocytes induces apoptosis, and some natural products enhance cell survival through PI3K/Akt/GSK3β regulation (phosphorylation). Akt, Ak strain transforming; ARE, antioxidant response element; BAX, Bcl2‐associated X protein; Bcl‐2, B-cell lymphoma 2; eNOS, endothelial nitric oxide synthase; GSK3β, glycogen synthase kinase 3 beta; HO-1, heme oxygenase-1; IKK, IκB kinase; JNK, c-Jun N-terminal kinase; mPTP, mitochondrial permeability transition pore; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Nrf2, nuclear factor erythroid 2-related factor; NO, Nitric oxide; PGC‑1α, peroxisome proliferator‑activated receptor γ coactivator‑1α; PI3K, Phosphoinositide 3-kinases; PKC, Protein kinase C; PKG, protein kinase G; ROS, reactive oxygen species; TNF-α, tumor necrosis factor-alpha; VEGF-B, vascular endothelial growth factor B.

Liu G, Zhang B-F, Hu Q, et al. Syringic acid mitigates myocardial ischemia reperfusion injury by activating the PI3K/Akt/GSK-3β signaling pathway. Biochem Biophys Res Commun. 2020;531(2):242–249.

 PubMed Web of Science ®Google Scholar

Chang W, Li K, Guan F, et al. Berberine pretreatment confers cardioprotection against ischemia–reperfusion injury in a rat model of type 2 diabetes. J Cardiovasc Pharmacol Ther. 2016;21(5):486–494.

 PubMed Web of Science ®Google Scholar

Kim SJ, Li M, Jeong CW, et al. Epigallocatechin-3-gallate, a green tea catechin, protects the heart against regional ischemia-reperfusion injuries through activation of RISK survival pathways in rats. Arch Pharm Res. 2014;37(8):1079–1085.

 PubMed Web of Science ®Google Scholar

Min J, Wei C. Hydroxysafflor yellow a cardioprotection in ischemia–reperfusion (I/R) injury mainly via Akt/hexokinase II independent of ERK/GSK-3β pathway. Biomed Pharmacother. 2017;87:419–426.

 PubMed Web of Science ®Google Scholar

Yang L, Zhang Y, Zhu M, et al. Resveratrol attenuates myocardial ischemia/reperfusion injury through up-regulation of vascular endothelial growth factor B. Free Radical Biol Med. 2016;101:1–9.

 PubMed Web of Science ®Google Scholar

Zhou M, Ren H, Han J, et al. Protective effects of Kaempferol against myocardial ischemia/reperfusion injury in isolated rat heart via antioxidant activity and inhibition of Glycogen Synthase Kinase-3 β. Oxid Med Cell Longevity. 2015;2015:1–8.

 Web of Science ®Google Scholar

Bharti S, Golechha M, Kumari S, et al. Akt/gsk-3β/eNOS phosphorylation arbitrates safranal-induced myocardial protection against ischemia–reperfusion injury in rats. Eur J Nutr. 2012;51(6):719–727.

 PubMed Web of Science ®Google Scholar

Wei D, Xu H, Gai X, et al. Astragaloside IV alleviates myocardial ischemia-reperfusion injury in rats through regulating PI3K/AKT/GSK-3β signaling pathways. Acta Cir Bras. 2019;34(7): e201900708.

 PubMed Web of Science ®Google Scholar

Wang D, Zhang X, Li D, et al. Kaempferide protects against myocardial ischemia/reperfusion injury through activation of the PI3K/Akt/GSK-3β pathway. Mediators Inflamm. 2017;2017:5278218.

 PubMed Web of Science ®Google Scholar

Wang Y, Li X, Wang X, et al. Ginsenoside Rd attenuates myocardial ischemia/reperfusion injury via Akt/GSK-3β signaling and inhibition of the mitochondria-dependent apoptotic pathway. PLoS ONE. 2013;8(8):e70956.

 PubMed Web of Science ®Google Scholar

Liao Z, Liu D, Tang L, et al. Long‐term oral resveratrol intake provides nutritional preconditioning against myocardial ischemia/reperfusion injury: involvement of VDAC1 downregulation. Mol Nutr Food Res. 2015;59(3):454–464.

 PubMed Web of Science ®Google Scholar

Shanmugam K, Ravindran S, Kurian GA, et al. Fisetin confers cardioprotection against myocardial ischemia reperfusion injury by suppressing mitochondrial oxidative stress and mitochondrial dysfunction and inhibiting glycogen synthase kinase 3β activity. Oxid Med Cell Longevity. 2018;2018:9173436.

 PubMed Web of Science ®Google Scholar

Xu L, Jiang X, Wei F, et al. Leonurine protects cardiac function following acute myocardial infarction through anti‑apoptosis by the PI3K/AKT/GSK3β signaling pathway. J Mol Med Rep. 2018;18(2):1582–1590.

 PubMed Web of Science ®Google Scholar

Duan L, Liang C, Li X, et al. Lycopene restores the effect of ischemic postconditioning on myocardial ischemia‑reperfusion injury in hypercholesterolemic rats. Int J Mol Med. 2019;43(6):2451–2461.

 PubMed Web of Science ®Google Scholar

Liu J, Li Y, Tang Y, et al. Rhein protects the myocardiac cells against hypoxia/reoxygenation-induced injury by suppressing GSK3β activity. Phytomedicine. 2018;51:1–6.

 PubMed Web of Science ®Google Scholar

Li X-L, Fan J-P, Liu J-X, et al. Salvianolic acid a protects neonatal cardiomyocytes against hypoxia/reoxygenation-induced injury by preserving mitochondrial function and activating Akt/GSK-3β signals. Chin J Integr Med. 2019;25(1):23–30.

 PubMed Web of Science ®Google Scholar

Wang S, Zhu Y, Qiu R. Shikonin protects H9C2 cardiomyocytes against hypoxia/reoxygenation injury through activation of PI3K/Akt signaling pathway. Biomed Pharmacother. 2018;104:712–717.

 PubMed Web of Science ®Google Scholar

Gu M, He P, Lyu C, et al. Spinosin and 6’’‘‑feruloylspinosin protect the heart against acute myocardial ischemia and reperfusion in rats. J Mol Med Rep. 2019;20(5):4253–4261.

 PubMed Web of Science ®Google Scholar

Zheng D, Liu Z, Zhou Y, et al. Urolithin B, a gut microbiota metabolite, protects against myocardial ischemia/reperfusion injury via p62/Keap1/Nrf2 signaling pathway. Pharmacol Res. 2020;153:104655.

 PubMed Web of Science ®Google Scholar

Tang L, Mo Y, Li Y, et al. Urolithin a alleviates myocardial ischemia/reperfusion injury via PI3K/Akt pathway. Biochem Biophys Res Commun. 2017;486(3):774–780.

 PubMed Web of Science ®Google Scholar

Data availability statement

Data sharing is not applicable to this article as no datasets were generated or analyzed.