Piperine protects against myocardial ischemia/reperfusion injury by activating the PI3K/AKT signaling pathway

Li,Yun-Peng; Chen,Zhen; Cai,Yu-Hua

doi:10.3892/etm.2021.9805

Piperine protects against myocardial ischemia/reperfusion injury by activating the PI3K/AKT signaling pathway

Authors:
- Yun-Peng Li
- Zhen Chen
- Yu-Hua Cai
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Affiliations: Department of Cardiovasology, Affiliated Dongfeng Hospital, Hubei University of Medicine, Shiyan, Hubei 442008, P.R. China, Department of Emergency and Evidence‑Based Medicine, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430014, P.R. China, Department of Cardiovasology, Jingzhou First Municipal Hospital, Jingzhou, Hubei 434000, P.R. China
Published online on: February 19, 2021 https://doi.org/10.3892/etm.2021.9805
Article Number: 374
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Piperine (PIP) exerts numerous pharmacological effects and its involvement in endoplasmic reticulum (ER) stress (ERS)‑led apoptosis has garnered attention. The present study focused on whether PIP played protective effects on hypoxia/reoxygenation (H/R)‑induced cardiomyocytes by repressing ERS‑led apoptosis. The potential molecular mechanisms in association with the PI3K/AKT signaling pathway were investigated. Primary neonatal rat cardiomyocytes (NRCMs) were isolated and randomized into four groups: control + vehicle group, control + PIP group, H/R + vehicle group and H/R + PIP group. The H/R injury model was constructed by 4 h of hypoxia induction followed by 6 h of reoxygenation. A total of 10 µM PI3K/AKT inhibitor LY294002 was supplemented to the cells during the experiments. Cell viability and myocardial enzymes were detected to evaluate myocardial damage. A flow cytometry assay was performed to assess apoptotic response. Western blot analysis was performed to detect the expression of related proteins including PI3K, AKT, CHOP, GRP78 and cleaved caspase‑12. The results showed that H/R markedly promoted myocardial damage as shown by the increased release of lactate dehydrogenase and creatine kinase levels, but a reduction in cell viability. In addition, ERS‑induced apoptosis was markedly promoted by H/R in NRCMs, as shown by the increased apoptotic rates and expression of C/EBP‑homologous protein, endoplasmic reticulum chaperone BiP and caspase‑12. PIP administration reversed cell injury and ERS‑induced apoptosis in H/R. Mechanistic studies concluded that the apoptosis‑inhibitory contributions and cardio‑favorable effects of PIP were caused partly by the activation of the PI3K/AKT signaling pathway, which was verified by LY294002 administration. To conclude, PIP can reduce ERS‑induced apoptosis by activating the PI3K/AKT signaling pathway during the process of H/R injury, which could be a potential therapeutic target for the treatment of myocardial ischemia/reperfusion injury.

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1	Zeng G, Lian C, Yang P, Zheng M, Ren H and Wang H: E3-ubiquitin ligase TRIM6 aggravates myocardial ischemia/reperfusion injury via promoting STAT1-dependent cardiomyocyte apoptosis. Aging (Albany NY). 11:3536–3550. 2019.PubMed/NCBI View Article : Google Scholar
2	Ruan Z, Wang S, Yu W and Deng F: LncRNA MALAT1 aggravates inflammation response through regulating PTGS2 by targeting miR-26b in myocardial ischemia-reperfusion injury. Int J Cardiol. 288(122)2019.PubMed/NCBI View Article : Google Scholar
3	Zhang BF, Jiang H, Chen J, Guo X, Li Y, Hu Q and Yang S: Nobiletin ameliorates myocardial ischemia and reperfusion injury by attenuating endoplasmic reticulum stress-associated apoptosis through regulation of the PI3K/AKT signal pathway. Int Immunopharmacol. 73:98–107. 2019.PubMed/NCBI View Article : Google Scholar
4	Chang JC, Lien CF, Lee WS, Chang HR, Hsu YC, Luo YP, Jeng JR, Hsieh JC and Yang KT: Intermittent intermittent hypoxia prevents myocardial mitochondrial Ca²⁺ overload and cell death during ischemia/reperfusion: The role of reactive oxygen species. Cells. 8: pii(E564)2019.PubMed/NCBI View Article : Google Scholar
5	Shu Z, Yang Y, Yang L, Jiang H, Yu X and Wang Y: Cardioprotective effects of dihydroquercetin against ischemia reperfusion injury by inhibiting oxidative stress and endoplasmic reticulum stress-induced apoptosis via the PI3K/Akt pathway. Food Funct. 10:203–215. 2019.PubMed/NCBI View Article : Google Scholar
6	Shen D, Chen R, Zhang L, Rao Z, Ruan Y, Li L, Chu M and Zhang Y: Sulodexide attenuates endoplasmic reticulum stress induced by myocardial ischaemia/reperfusion by activating the PI3K/Akt pathway. J Cell Mol Med. 23:5063–5075. 2019.PubMed/NCBI View Article : Google Scholar
7	Manayi A, Nabavi SM, Setzer WN and Jafari S: Piperine as a potential anti-cancer agent: A review on preclinical studies. Curr Med Chem. 25:4918–4928. 2018.PubMed/NCBI View Article : Google Scholar
8	Abdel-Daim MM, Sayed AA, Abdeen A, Aleya L, Ali D, Alkahtane AA, Alarifi S and Alkahtani S: Piperine enhances the antioxidant and anti-inflammatory activities of thymoquinone against Microcystin-LR-induced hepatotoxicity and neurotoxicity in mice. Oxid Med Cell Longev. 2019(1309175)2019.PubMed/NCBI View Article : Google Scholar
9	Zou Y, Gong P, Zhao W, Zhang J, Wu X, Xin C, Xiong Z, Li Z, Wu X, Wan Q, et al: Quantitative iTRAQ-based proteomic analysis of piperine protected cerebral ischemia/reperfusion injury in rat brain. Neurochem Int. 124:51–61. 2019.PubMed/NCBI View Article : Google Scholar
10	Vaibhav K, Shrivastava P, Javed H, Khan A, Ahmed ME, Tabassum R, Khan MM, Khuwaja G, Islam F, Siddiqui MS, et al: Piperine suppresses cerebral ischemia-reperfusion-induced inflammation through the repression of COX-2, NOS-2, and NF-κB in middle cerebral artery occlusion rat model. Mol Cell Biochem. 367:73–84. 2012.PubMed/NCBI View Article : Google Scholar
11	Zeng Y and Yang Y: Piperine depresses the migration progression via downregulating the Akt/mTOR/MMP-9 signaling pathway in DU145 cells. Mol Med Rep. 17:6363–6370. 2018.PubMed/NCBI View Article : Google Scholar
12	Ma ZG, Yuan YP, Zhang X, Xu SC, Wang SS and Tang QZ: Piperine attenuates pathological cardiac fibrosis via PPAR-γ/AKT pathways. Ebiomedicine. 18:179–187. 2017.PubMed/NCBI View Article : Google Scholar
13	Chen X, Ge F, Liu J, Bao S, Chen Y, Li D, Li Y, Huang T, Chen X, Zhu Q, et al: Diverged effects of piperine on testicular development: Stimulating leydig cell development but inhibiting spermatogenesis in rats. Front Pharmacol. 9(244)2018.PubMed/NCBI View Article : Google Scholar
14	Hu S, Cheng M, Guo X, Wang S, Liu B, Jiang H, Huang C and Wu G: Down-regulation of miR-200c attenuates AngII-induced cardiac hypertrophy via targeting the MLCK-mediated pathway. J Cell Mol Med. 23:2505–2516. 2019.PubMed/NCBI View Article : Google Scholar
15	Cheng F, Yuan W, Cao M, Chen R, Wu X and Yan J: Cyclophilin a protects cardiomyocytes against hypoxia/reoxygenation-induced apoptosis via the AKT/Nox2 pathway. Oxid Med Cell Longev. 2019(2717986)2019.PubMed/NCBI View Article : Google Scholar
16	Guo X, Jiang H, Chen J, Zhang BF, Hu Q, Yang S, Yang J and Zhang J: RP105 ameliorates hypoxia̸reoxygenation injury in cardiac microvascular endothelial cells by suppressing TLR4̸MAPKs̸NF-κB signaling. Int J Mol Med. 42:505–513. 2018.PubMed/NCBI View Article : Google Scholar
17	Sun Y, Liu L, Yuan J, Sun Q, Wang N and Wang Y: RP105 protects PC12 cells from oxygenglucose deprivation/reoxygenation injury via activation of the PI3K/AKT signaling pathway. Int J Mol Med. 41:3081–3089. 2018.PubMed/NCBI View Article : Google Scholar
18	Guo J, Cui Y, Liu Q, Yang Y, Li Y, Weng L, Tang B, Jin P, Li XJ, Yang S and Li S: Piperine ameliorates SCA17 neuropathology by reducing ER stress. Mol Neurodegener. 13(4)2018.PubMed/NCBI View Article : Google Scholar
19	Hammad AS, Ravindran S, Khalil A and Munusamy S: Structure-activity relationship of piperine and its synthetic amide analogs for therapeutic potential to prevent experimentally induced ER stress in vitro. Cell Stress Chaperones. 22:417–428. 2017.PubMed/NCBI View Article : Google Scholar
20	Peng X, Yang T, Liu G, Liu H, Peng Y and He L: Piperine ameliorated lupus nephritis by targeting AMPK-mediated activation of NLRP3 inflammasome. Int Immunopharmacol. 65:448–457. 2018.PubMed/NCBI View Article : Google Scholar
21	Hsieh TY, Chang Y and Wang SJ: Piperine-mediated suppression of voltage-dependent Ca²⁺ influx and glutamate release in rat hippocampal nerve terminals involves 5HT1A receptors and G protein βγ activation. Food Funct. 10:2720–2728. 2019.PubMed/NCBI View Article : Google Scholar
22	Singh S and Kumar P: Piperine in combination with quercetin halt 6-OHDA induced neurodegeneration in experimental rats: Biochemical and neurochemical evidences. Neurosci Res. 133:38–47. 2018.PubMed/NCBI View Article : Google Scholar
23	George K, Thomas NS and Malathi R: Piperine blocks voltage gated K⁺ current and inhibits proliferation in androgen sensitive and insensitive human prostate cancer cell lines. Arch Biochem Biophys. 667:36–48. 2019.PubMed/NCBI View Article : Google Scholar
24	Dhivya V, Priya LB, Chirayil HT, Sathiskumar S, Huang CY and Padma VV: Piperine modulates isoproterenol induced myocardial ischemia through antioxidant and anti-dyslipidemic effect in male Wistar rats. Biomed Pharmacother. 87:705–713. 2017.PubMed/NCBI View Article : Google Scholar
25	Yaffe PB, Power Coombs MR, Doucette CD, Walsh M and Hoskin DW: Piperine, an alkaloid from black pepper, inhibits growth of human colon cancer cells via G1 arrest and apoptosis triggered by endoplasmic reticulum stress. Mol Carcinog. 54:1070–1085. 2015.PubMed/NCBI View Article : Google Scholar
26	Deng T, Wang Y, Wang C and Yan H: FABP4 silencing ameliorates hypoxia reoxygenation injury through the attenuation of endoplasmic reticulum stress-mediated apoptosis by activating PI3K/Akt pathway. Life Sci. 224:149–156. 2019.PubMed/NCBI View Article : Google Scholar