Adropin reduces hypoxia/reoxygenation‑induced myocardial injury via the reperfusion injury salvage kinase pathway

Wu,Lingzhen; Fang,Jun; Yuan,Xun; Xiong,Chang; Chen,Lianglong

doi:10.3892/etm.2019.7937

Adropin reduces hypoxia/reoxygenation‑induced myocardial injury via the reperfusion injury salvage kinase pathway

Authors:
- Lingzhen Wu
- Jun Fang
- Xun Yuan
- Chang Xiong
- Lianglong Chen
View Affiliations

Affiliations: Department of Cardiology, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, P.R. China
Published online on: August 26, 2019 https://doi.org/10.3892/etm.2019.7937
Pages: 3307-3314
Copyright: © Wu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Adropin is a secreted polypeptide that has been demonstrated to serve an important role in protecting the vascular endothelium. Pharmacological activation of pro‑survival kinases, such as PI3K‑Akt and ERK1/2, are involved in the reperfusion injury salvage kinase (RISK) pathway. In the present study, the effects of adropin in cardiomyocyte injury induced by simulated ischemia/reperfusion (SI/R) were assessed. Additionally, the current study also assessed the mechanisms that govern SI/R in a H9c2 cardiomyoblast cell model. Cell viability was measured using an MTT assay. Cell injury was assessed using creatine kinase MB measurements. Apoptosis was assessed using flow cytometry and caspase‑3 activity. The inflammatory response was measured using tumor necrosis factor α and interleukin‑10 expression. Oxidative stress was assessed using malondialdehyde and superoxide dismutase. The expression levels of Akt, ERK1/2, glycogen synthase kinase 3β (GSK3β), Bcl‑2 and Bax were determined using western blot analysis. The results of the current study revealed that moderate‑dose adropin increased cell viability, reduced early apoptosis and caspase‑3 activity, promoted Bcl‑2 expression, inhibited Bax and increased the Bcl‑2/Bax ratio. Adropin significantly increased the phosphorylation of Akt, ERK1/2 and GSK3β, whereas inhibitors of PI3K and ERK1/2, respectively, LY294002 and PD98059, abolished the cardioprotective role of adropin. Furthermore, no significant difference was observed in phosphorylated‑STAT3/total‑STAT3 expression between the adropin and SI/R groups and Janus kinase 2 inhibitor AG490 did not significantly inhibit the protective role of adropin. These results indicate that adropin exerts a protective effect against SI/R injury through the RISK pathway instead of the survivor activating factor enhancement pathway.

View Figures

View References

1	Hausenloy DJ and Yellon DM: Myocardial ischemia-reperfusion injury: A neglected therapeutic target. J Clin Invest. 123:92–100. 2013. View Article : Google Scholar : PubMed/NCBI
2	Chandrasekar B, Smith JB and Freeman GL: Ischemia-reperfusion of rat myocardium activates nuclear factor-KappaB and induces neutrophil infiltration via lipopolysaccharide-induced CXC chemokine. Circulation. 103:2296–2302. 2001. View Article : Google Scholar : PubMed/NCBI
3	Kaminski KA, Bonda TA, Korecki J and Musial WJ: Oxidative stress and neutrophil activation-the two keystones of ischemia/reperfusion injury. Int J Cardiol. 86:41–59. 2002. View Article : Google Scholar : PubMed/NCBI
4	Eefting F, Rensing B, Wigman J, Pannekoek WJ, Liu WM, Cramer MJ, Lips DJ and Doevendans PA: Role of apoptosis in reperfusion injury. Cardiovasc Res. 61:414–426. 2004. View Article : Google Scholar : PubMed/NCBI
5	Kumar KG, Trevaskis JL, Lam DD, Sutton GM, Koza RA, Chouljenko VN, Kousoulas KG, Rogers PM, Kesterson RA, Thearle M, et al: Identification of adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell Metab. 8:468–481. 2008. View Article : Google Scholar : PubMed/NCBI
6	Lovren F, Pan Y, Quan A, Singh KK, Shukla PC, Gupta M, Al-Omran M, Teoh H and Verma S: Adropin is a novel regulator of endothelial function. Circulation 122 (11 Suppl). S185–S192. 2010. View Article : Google Scholar
7	Butler AA, Tam CS, Stanhope KL, Wolfe BM, Ali MR, O'Keeffe M, St-Onge MP, Ravussin E and Havel PJ: Low circulating adropin concentrations with obesity and aging correlate with risk factors for metabolic disease and increase after gastric bypass surgery in humans. J Clin Endocrinol Metab. 97:3783–3791. 2012. View Article : Google Scholar : PubMed/NCBI
8	Celik A, Balin M, Kobat MA, Erdem K, Baydas A, Bulut M, Altas Y and Aydin S and Aydin S: Deficiency of a new protein associated with cardiac syndrome X; called adropin. Cardiovasc Ther. 31:174–178. 2013. View Article : Google Scholar : PubMed/NCBI
9	Wu L, Fang J, Chen L, Zhao Z, Luo Y, Lin C and Fan L: Low serum adropin is associated with coronary atherosclerosis in type 2 diabetic and non-diabetic patients. Clin Chem Lab Med. 52:751–758. 2014. View Article : Google Scholar : PubMed/NCBI
10	Yang C, DeMars KM, Hawkins KE and Candelario-Jalil E: Adropin reduces paracellular permeability of rat brain endothelial cells exposed to ischemia-like conditions. Peptides. 81:29–37. 2016. View Article : Google Scholar : PubMed/NCBI
11	Tanaka M, Ito H, Adachi S, Akimoto H, Nishikawa T, Kasajima T, Marumo F and Hiroe M: Hypoxia induces apoptosis with enhanced expression of Fas antigen messenger RNA in cultured neonatal rat cardiomyocytes. Circ Res. 75:426–433. 1994. View Article : Google Scholar : PubMed/NCBI
12	Singla DK, Singla RD and McDonald DE: Factors released from embryonic stem cells inhibit apoptosis in H9c2 cells through PI3K/Akt but not ERK pathway. Am J Physiol Heart Circ Physiol. 295:H907–H913. 2008. View Article : Google Scholar : PubMed/NCBI
13	Ogata Y, Takahashi M, Ueno S, Takeuchi K, Okada T, Mano H, Ookawara S, Ozawa K, Berk BC, Ikeda U, et al: Antiapoptotic effect of endothelin-1 in rat cardiomyocytes in vitro. Hypertension. 41:1156–1163. 2003. View Article : Google Scholar : PubMed/NCBI
14	Scarabelli TM, Knight R, Stephanou A, Townsend P, Chen-Scarabelli C, Lawrence K, Gottlieb R, Latchman D and Narula J: Clinical implications of apoptosis in ischemic myocardium. Curr Probl Cardiol. 31:181–264. 2006. View Article : Google Scholar : PubMed/NCBI
15	Pchejetski D, Kunduzova O, Dayon A, Calise D, Seguelas MH, Leducq N, Seif I, Parini A and Cuvillier O: Oxidative stress-dependent sphingosine kinase-1 inhibition mediates monoamine oxidase A-associated cardiac cell apoptosis. Circ Res. 100:41–49. 2007. View Article : Google Scholar : PubMed/NCBI
16	Fu J, Huang H, Liu J, Pi R, Chen J and Liu P: Tanshinone IIA protects cardiac myocytes against oxidative stress-triggered damage and apoptosis. Eur J Pharmacol. 568:213–221. 2007. View Article : Google Scholar : PubMed/NCBI
17	Song JQ, Teng X, Cai Y, Tang CS and Qi YF: Activation of Akt/GSK-3beta signaling pathway is involved in intermedin(1–53) protection against myocardial apoptosis induced by ischemia/reperfusion. Apoptosis. 14:1299–1307. 2009. View Article : Google Scholar : PubMed/NCBI
18	Frangogiannis NG, Smith CW and Entman ML: The inflammatory response in myocardial infarction. Cardiovasc Res. 53:31–47. 2002. View Article : Google Scholar : PubMed/NCBI
19	Marx N, Neumann FJ, Ott I, Gawaz M, Koch W, Pinkau T and Schömig A: Induction of cytokine expression in leukocytes in acute myocardial infarction. J Am Coll Cardiol. 30:165–170. 1997. View Article : Google Scholar : PubMed/NCBI
20	Kumar D and Jugdutt BI: Apoptosis and oxidants in the heart. J Lab Clin Med. 142:288–297. 2003. View Article : Google Scholar : PubMed/NCBI
21	Kumar D, Lou H and Singal PK: Oxidative stress and apoptosis in heart dysfunction. Herz. 27:662–668. 2002. View Article : Google Scholar : PubMed/NCBI
22	Zhao ZQ: Oxidative stress-elicited myocardial apoptosis during reperfusion. Curr Opin Pharmacol. 4:159–165. 2004. View Article : Google Scholar : PubMed/NCBI
23	Liang R, Zhao Q, Jian G, Cheng D, Wang N, Zhang G and Wang F: Tanshinone IIA attenuates contrast-induced nephropathy via Nrf2 activation in rats. Cell Physiol Biochem. 46:2616–2623. 2018. View Article : Google Scholar : PubMed/NCBI
24	Kong Y, Yin J, Cheng D, Lu Z, Wang N, Wang F and Liang M: Antithrombin III attenuates AKI following acute severe pancreatitis. Shock. 49:572–579. 2018. View Article : Google Scholar : PubMed/NCBI
25	Yellon DM and Hausenloy DJ: Myocardial reperfusion injury. N Engl J Med. 357:1121–1135. 2007. View Article : Google Scholar : PubMed/NCBI
26	Ovize M, Baxter GF, Di Lisa F, Ferdinandy P, Garcia-Dorado D, Hausenloy DJ, Heusch G, Vinten-Johansen J, Yellon DM and Schulz R; Working Group of Cellular Biology of Heart of European Society of Cardiology, : Postconditioning and protection from reperfusion injury: Where do we stand? Position paper from the working group of cellular biology of the heart of the European Society of Cardiology. Cardiovasc Res. 87:406–423. 2010. View Article : Google Scholar : PubMed/NCBI
27	Hausenloy DJ and Yellon DM: New directions for protecting the heart against ischaemia-reperfusion injury: Targeting the reperfusion injury salvage kinase (RISK)-pathway. Cardiovasc Res. 61:448–460. 2004. View Article : Google Scholar : PubMed/NCBI
28	Zhu M, Feng J, Lucchinetti E, Fischer G, Xu L, Pedrazzini T, Schaub MC and Zaugg M: Ischemic postconditioning protects remodeled myocardium via the PI3K-PKB/Akt reperfusion injury salvage kinase pathway. Cardiovasc Res. 72:152–162. 2006. View Article : Google Scholar : PubMed/NCBI
29	Armstrong SC: Protein kinase activation and myocardial ischemia/reperfusion injury. Cardiovasc Res. 61:427–436. 2004. View Article : Google Scholar : PubMed/NCBI
30	Mullonkal CJ and Toledo-Pereyra LH: Akt in ischemia and reperfusion. J Invest Surg. 20:195–203. 2007. View Article : Google Scholar : PubMed/NCBI
31	Jeong JJ, Ha YM, Jin YC, Lee EJ, Kim JS, Kim HJ, Seo HG, Lee JH, Kang SS, Kim YS and Chang KC: Rutin from Lonicera japonica inhibits myocardial ischemia/reperfusion-induced apoptosis in vivo and protects H9c2 cells against hydrogen peroxide-mediated injury via ERK1/2 and PI3K/Akt signals in vitro. Food Chem Toxicol. 47:1569–1576. 2009. View Article : Google Scholar : PubMed/NCBI
32	Lacerda L, Somers S, Opie LH and Lecour S: Ischaemic postconditioning protects against reperfusion injury via the SAFE pathway. Cardiovasc Res. 84:201–208. 2009. View Article : Google Scholar : PubMed/NCBI
33	Lecour S: Activation of the protective survivor activating factor enhancement (SAFE) pathway against reperfusion injury: Does it go beyond the RISK pathway? J Mol Cell Cardiol. 47:32–40. 2009. View Article : Google Scholar : PubMed/NCBI