The protective effect of Apelin-13 against cardiac hypertrophy through activating the PI3K-AKT-mTOR signaling pathway

Document Type : Original Article

Authors

1 Provincial Clinical Medical College of Fujian Medical University, Fuzhou 350001, Fujian, China

2 Department of Cardiovascular Medicine, Fujian Provincial Hospital South Branch (Fujian Provincial Jinshan Hospital), Fuzhou 350028, Fujian, China

3 Department of Geriatric Medicine, Fujian Provincial Hospital, Fuzhou 350001, Fujian, China

4 Fujian Provincial Institute of Clinical Geriatrics, Fujian Key Laboratory of Geriatrics, Fujian Provincial Center for Geriatrics, Fuzhou, 350001, Fujian, China

Abstract

Objective(s): To determine the protective effect of Apelin-13 on cardiac hypertrophy through activating the PI3K-AKT-mTOR signaling pathway.
Materials and Methods: The phenylephrine-induced cardiomyocyte hypertrophy model was established in H9C2 cells in vitro. Electroporation transfection technology was utilized to prepare and screen the H9C2 cells inducing low expression of the angiotensin type one receptor-related protein (Si-APJ). H9C2 and Si-APJ cells were divided independently into five groups: the control group, the PE group, the PE+Apelin group, the PE+Rapa group, and the PE+Apelin+Rapa group. RT-PCR was performed to analyze the mRNA expression levels of myosin heavy chain 7 (MYH7). Expression of the PI3K/AKT/mTOR pathway proteins and MYH7 was investigated by western blot.
Results: The expression of PI3K/AKT/mTOR phosphorylated proteins was significantly higher in the PE group compared with the PE+Apelin group in H9C2 cells (P<0.05). Conversely, in Si-APJ H9C2 cells, the expression of PI3K/AKT/mTOR phosphorylated proteins was decreased (P<0.05). In H9C2 cells, the expression of MYH7 protein was increased in the PE group compared with the control group (P<0.05). In the same cell line, the expression of MYH7 in the PE+Apelin group was decreased significantly compared with the PE group (P<0.05). In Si-APJ H9C2 cells, compared with the control group, the expression of MYH7 in the PE group still increased significantly (P<0.05). In contrast, in the same cell line, there was no statistically significant difference in MYH7 expression between the PE+Apelin, PE+Rapa, and PE+Apelin+Rapa groups compared to the PE group (P>0.05).
Conclusion: Apelin-13 reduces PE-induced cardiac hypertrophy by activating the PI3K/AKT/mTOR signaling pathway.

Keywords

References

1. Ashley EA, Powers J, Chen M, Kundu R, Finsterbach T, Caffarelli A, et al. The endogenous peptide apelin potently improves cardiac contractility and reduces cardiac loading in vivo. Cardiovasc Res 2005; 65:73-82.
2. Zhang ZZ, Wang W, Jin HY, Chen X, Cheng YW, Xu YL,                et al. Apelin is a negative regulator of angiotensin II-mediated adverse myocardial remodeling and dysfunction. Hypertension 2017;70:1165-1175.
3. Nakamura M, Sadoshima J. Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol 2018;15:387-407.
4. Gallo S, Vitacolonna A, Bonzano A, Comoglio P, Crepaldi T. ERK: A key player in the pathophysiology of cardiac hypertrophy. Int J Mol Sci 2019;20:2164. 
5. Tham YK, Bernardo BC, Ooi JY, Weeks KL, McMullen JR. Pathophysiology of cardiac hypertrophy and heart failure: Signaling pathways and novel therapeutic targets. Arch Toxicol 2015; 89:1401-1438. 
6. Lee CY, Park HK, Lee BS, et al. Novel therapeutic effects of pterosin B on Ang II-induced cardiomyocyte hypertrophy. Molecules 2020; 25:5279. 
7. Ba L, Gao J, Chen Y, Jeong S, Hyun SA, Choi JW, et al. Allicin attenuates pathological cardiac hypertrophy by inhibiting autophagy via activation of PI3K/Akt/mTOR and MAPK/ERK/mTOR signaling pathways. Phytomedicine 2019;58:152765. 
8. Pei H, Wang W, Zhao D, Su H, Su G, Zhao Z. G protein-coupled estrogen receptor 1 inhibits angiotensin II-induced cardiomyocyte hypertrophy via the regulation of PI3K-Akt-mTOR signalling and autophagy. Int J Biol Sci 2019; 15:81-92.
9. Weeks KL, Bernardo BC, Ooi JYY, Patterson NL, McMullen JR. The IGF1-PI3K-Akt signaling pathway in mediating exercise-induced cardiac hypertrophy and protection. Adv Exp Med Biol 2017;1000:187-210. 
10. Latres E, Amini AR, Amini AA, Griffiths J, Martin FJ, Wei Y, et al. Insulin-like growth factor-1 (IGF-1) inversely regulates atrophy-induced genes via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway. J Biol Chem 2005; 280:2737-2744. 
11. Chen G, Pan SQ, Shen C, Pan SHF, Zhang XM, He QY. Puerarin inhibits angiotensin II-induced cardiac hypertrophy via the redox-sensitive ERK1/2, p38 and NF-κB pathways. Acta Pharmacol Sin 2014; 35:463-475.
12. Baghaiee B, Karimi P, Siahkouhian M, Pescatello LS. Moderate aerobic exercise training decreases middle-aged induced pathologic cardiac hypertrophy by improving Klotho expression, MAPK signaling pathway, and oxidative stress status in Wistar rats. Iran J Basic Med Sci 2018; 21:911-919.
13. Zhang Q, Wang F, Wang F, Wu N. Long noncoding RNA MAGI1-IT1 regulates cardiac hypertrophy by modulating miR-302e/DKK1/Wnt/beta-catenin signaling pathway. J Cell Physiol 2020; 235:245-253.
14. Khalilimeybodi A, Daneshmehr A, Sharif Kashani B. Ca2+-dependent calcineurin/ NFAT signaling in β-adrenergic-induced cardiac hypertrophy. Gen Physiol Biophys 2018; 37: 41-56. 
15. Cui J, Zhang F, Wang Y, et al. Macrophage migration inhibitory factor promotes cardiac stem cell proliferation and endothelial differentiation through the activation of the PI3K/Akt/mTOR and AMPK pathways. Int J Mol Med 2016; 37:1299-1309. 
16. Patel SS, Acharya A, Ray RS, Liu J, Ming X, Hou J, et al. Cellular and molecular mechanisms of curcumin in prevention and treatment of disease. Crit Rev Food Sci Nutr 2020; 60:887-939. 
17. Ke Z, Wang G, Yang L, Qiu H, Wu H, Du M, et al. Crude terpene glycoside component from Radix paeoniae rubra protects against isoproterenol-induced myocardial ischemic injury via activation of the PI3K/AKT/mTOR signaling pathway. J Ethnopharmacol. 2017; 206:160-169.
18. Liu Y, Li S, Gao Z, Li SH, Tan Q, Li Y, et al. Indoleamine 2, 3-dioxygenase 1 (IDO1) promotes cardiac hypertrophy via a PI3K-AKT-mTOR-dependent mechanism. Cardiovasc Toxicol 2021; 21: 655-668.
19. Carpéné C, Dray C, Attané C, Valet P, Portillo MP, Churruca I, et al. Expanding role for the apelin/APJ system in physiopathology. J Physiol Biochem 2007;63: 359-373.
20. Dawid M, Mlyczyńska E, Jurek M, Respekta N, Pich K, Kurowska P, et al. Apelin, APJ, and ELABELA: Role in placental function, pregnancy, and foetal development-an overview. Cells 2021; 11:99
21. Yu XH, Tang ZB, Liu LJ, Qian H, Tang SHL, Zhang DW, et al. Apelin and its receptor APJ in cardiovascular diseases. Clin Chim Acta 2014; 428:1-8.
22. Chagnon F, Coquerel D, Salvail D, Marsault E, Dumaine R, Auger-Messier M, et al. Apelin compared with dobutamine exerts cardioprotection and extends survival in a rat model of endotoxin-induced myocardial dysfunction. Crit Care Med 2017; 45:e391-e398.
23. Paoletti E, De Nicola L, Gabbai FB, Chiodini P, Ravera M, Pieracci L, et al. Associations of left ventricular hypertrophy and geometry with adverse outcomes in patients with CKD and hypertension. Clin J Am Soc Nephrol 2016; 11:271-279.
24. Shende P, Xu L, Morandi C, Pentassuglia L, Heim PH, Lebboukh S, et al. Cardiac mTOR complex 2 preserves ventricular function in pressure-overload hypertrophy. Cardiovascular Research 2016; 109:103-114.
25. Anestopoulos I, Kavo A, Tentes I, Kortsaris A, Panayiotidis M, Lazou A, et al. Silibinin protects H9C2 cardiac cells from oxidative stress and inhibits phenylephrine-induced hypertrophy: Potential mechanisms. J Nutr Biochem 2013; 24:586-594.
26. Sciarretta S, Zhai P, Maejima Y, Re DPD, Nagarajan N, Yee D, et al. mTORC2 regulates cardiac response to stress by inhibiting MST1. Cell Rep 2015; 11:125-136.
27. Sato T, Suzuki T, Watanabe H, Kadowaki A, Fukamizu A, Liu PP, et al. Apelin is a positive regulator of ACE2 in failing hearts. J Clin Invest 2013; 123:5203-5211.
28. Chen Y, Pan R, Zhang J, Liang T, Guo J, Sun T, et al. Pinoresinol diglucoside (PDG) attenuates cardiac hypertrophy via AKT/mTOR/NF-κB signaling in pressure overload-induced rats. J Ethnopharmacol 2021; 272:113920.
29. Gao L, Guo Y, Liu X, Shang D, Du Y. KLF15 protects against isoproterenol-induced cardiac hypertrophy via regulation of cell death and inhibition of Akt/mTOR signaling. Biochem Biophys Res Commun 2017; 487:22-27.
30. Gao W, Guo N, Zhao S, Chen Z,Zhang W, Yan F, et al. HTR2A promotes the development of cardiac hypertrophy by activating PI3K-PDK1-AKT-mTOR signaling. Cell Stress Chaperones 2020; 25:899-908.
Iranian Journal of Basic Medical Sciences
Volume 26, Issue 2
February 2023
Pages 183-189

Files

Share

How to cite

Statistics