Postconditioning attenuates myocardial ischemia‑reperfusion injury by inhibiting complement activation and upregulation of miR‑499

Huang,Zheng; He,Yan; Li,Qing-Jie; Wen,Hong; Zhang,Xin-Yue; Tu,Rong-Hui; Zhong,Guo-Qiang

doi:10.3892/etm.2021.10116

Postconditioning attenuates myocardial ischemia‑reperfusion injury by inhibiting complement activation and upregulation of miR‑499

Authors:
- Zheng Huang
- Yan He
- Qing-Jie Li
- Hong Wen
- Xin-Yue Zhang
- Rong-Hui Tu
- Guo-Qiang Zhong
View Affiliations

Affiliations: Department of Cardiology, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China, Department of Geriatric Cardiology, First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
Published online on: April 26, 2021 https://doi.org/10.3892/etm.2021.10116
Article Number: 684
Copyright: © Huang 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

The complement system plays a vital role in myocardial ischemia/reperfusion (I/R) injury. microRNA (miR)‑499 is involved in the cardioprotection of ischemic postconditioning (IPostC). The present study aimed to study the role of the complement system and miR‑499 in IPostC. Rat hearts were subjected to coronary ligation for 30 min, followed by reperfusion for 2 h. IPostC was introduced at the onset of reperfusion with three cycles of reperfusion for 30 sec and coronary artery occlusion for 30 sec. To study the role of miR‑499 in IPostC, adeno‑associated virus (AAV) vectors of miR‑499‑5p (AAV‑miR‑499‑5p) and miR‑499‑5p‑sponge (AAV‑miR‑499‑5p‑sponge) were transfected via tail vein injection, followed by IPostC protocols. Cardiac injury as well as the status of local and systemic complement activation and inflammation were assessed. IPostC significantly attenuated I/R‑induced rat cardiomyocyte apoptosis and the myocardial infarct size. These beneficial effects were accompanied by decreased local and circulating complement component (C)3a and C5a levels, decreased inflammatory marker expression, decreased NF‑κB signaling and increased cardiac miR‑499 expression. AAV‑miR‑499‑5p prevented local and systemic complement activation and inflammation as well as enhanced the cardioprotection of IPostC, whereas AAV‑miR‑499‑5p‑sponge produced the opposite effects. In summary, IPostC protected the rat myocardium against I/R injury, by inhibiting local and systemic complement activation; inflammation; NF‑κB signaling; and upregulation of miR‑499. As such, miR‑499 may have a critical role in IPostC‑mediated cardioprotection against I/R injury.

View Figures

View References

1	Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, Caforio ALP, Crea F, Goudevenos JA, Halvorsen S, et al: 2017 ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 39:119–177. 2018.PubMed/NCBI View Article : Google Scholar
2	Neri M, Riezzo I, Pascale N, Pomara C and Turillazzi E: Ischemia/reperfusion injury following acute myocardial infarction: A critical issue for clinicians and forensic pathologists. Mediators Inflamm. 2017(7018393)2017.PubMed/NCBI View Article : Google Scholar
3	Tang K, Cheng Y, Wu S, Liu L and Cheng L: Protective effect of C5 shRNA on myocardial ischemia-reperfusion injury in rats. Can J Physiol Pharmacol. 90:1394–1402. 2012.PubMed/NCBI View Article : Google Scholar
4	Frangogiannis NG: The inflammatory response in myocardial injury, repair, and remodelling. Nat Rev Cardiol. 11:255–265. 2014.PubMed/NCBI View Article : Google Scholar
5	Chun N, Haddadin AS, Liu J, Hou Y, Wong KA, Lee D, Rushbrook JI, Gulaya K, Hines R, Hollis T, et al: Activation of complement factor B contributes to murine and human myocardial ischemia/reperfusion injury. PLoS One. 12(e0179450)2017.PubMed/NCBI View Article : Google Scholar
6	Bardhan M and Kaushik R: Physiology, complement cascade. In: StatPearls, Treasure Island, FL, 2021.
7	Busche MN and Stahl GL: Role of the complement components C5 and C3a in a mouse model of myocardial ischemia and reperfusion injury. Ger Med Sci. 8(Doc20)2010.PubMed/NCBI View Article : Google Scholar
8	Fu J, Lin G, Wu Z, Ceng B, Wu Y, Liang G, Qin G, Li J, Chiu I and Liu D: Anti-apoptotic role for C1 inhibitor in ischemia/reperfusion-induced myocardial cell injury. Biochem Biophys Res Commun. 349:504–512. 2006.PubMed/NCBI View Article : Google Scholar
9	Pavlov VI, Tan YS, McClure EE, La Bonte LR, Zou C, Gorsuch WB and Stahl GL: Human mannose-binding lectin inhibitor prevents myocardial injury and arterial thrombogenesis in a novel animal model. Am J Pathol. 185:347–355. 2015.PubMed/NCBI View Article : Google Scholar
10	Hao M, Zhu S, Hu L, Zhu H, Wu X and Li Q: Myocardial ischemic postconditioning promotes autophagy against ischemia reperfusion injury via the activation of the nNOS/AMPK/mTOR Pathway. Int J Mol Sci. 18(614)2017.PubMed/NCBI View Article : Google Scholar
11	Khan AR, Binabdulhak AA, Alastal Y, Khan S, Faricy-Beredo BM, Luni FK, Lee WM, Khuder S and Tinkel J: Cardioprotective role of ischemic postconditioning in acute myocardial infarction: A systematic review and meta-analysis. Am Heart J. 168:512–521.e4. 2014.PubMed/NCBI View Article : Google Scholar
12	Aslan G, Gul HF, Tektemur A and Sahna E: Ischemic postconditioning reduced myocardial ischemia-reperfusion injury: The roles of melatonin and uncoupling protein 3. Anatol J Cardiol. 23:19–27. 2020.PubMed/NCBI View Article : Google Scholar
13	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004.PubMed/NCBI View Article : Google Scholar
14	Li Y, Lu J, Bao X, Wang X, Wu J, Li X and Hong W: MiR-499-5p protects cardiomyocytes against ischaemic injury via anti-apoptosis by targeting PDCD4. Oncotarget. 7:35607–35617. 2016.PubMed/NCBI View Article : Google Scholar
15	Wang JX, Jiao JQ, Li Q, Long B, Wang K, Liu JP, Li YR and Li PF: miR-499 regulates mitochondrial dynamics by targeting calcineurin and dynamin-related protein-1. Nat Med. 17:71–78. 2011.PubMed/NCBI View Article : Google Scholar
16	Zhu J, Yao K, Wang Q, Guo J, Shi H, Ma L, Liu H, Gao W, Zou Y and Ge J: Ischemic postconditioning-regulated miR-499 protects the rat heart against ischemia/reperfusion injury by inhibiting apoptosis through PDCD4. Cell Physiol Biochem. 39:2364–2380. 2016.PubMed/NCBI View Article : Google Scholar
17	Zhong GQ, Tu RH, Zeng ZY, Li QJ, He Y, Li S, He Y and Xiao F: Novel functional role of heat shock protein 90 in protein kinase C-mediated ischemic postconditioning. J Surg Res. 189:198–206. 2014.PubMed/NCBI View Article : Google Scholar
18	Fan JJ, Gao B, Song AQ, Zhu YJ, Zhou J, Li WZ, Yin YY and Wu WN: Spinal cord NLRP1 inflammasome contributes to dry skin induced chronic itch in mice. J Neuroinflammation. 17(122)2020.PubMed/NCBI View Article : Google Scholar
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
20	Haddad A and Wilson AM: Biochemistry, complement. In: StatPearls, Treasure Island, FL, 2021.
21	Shahini N, Michelsen AE, Nilsson PH, Ekholt K, Gullestad L, Broch K, Dahl CP, Aukrust P, Ueland T, Mollnes TE, et al: The alternative complement pathway is dysregulated in patients with chronic heart failure. Sci Rep. 7(42532)2017.PubMed/NCBI View Article : Google Scholar
22	Mocco J, Mack WJ, Ducruet AF, Sosunov SA, Sughrue ME, Hassid BG, Nair MN, Laufer I, Komotar RJ, Claire M, et al: Complement component C3 mediates inflammatory injury following focal cerebral ischemia. Circ Res. 99:209–217. 2006.PubMed/NCBI View Article : Google Scholar
23	Danobeitia JS, Ziemelis M, Ma X, Zitur LJ, Zens T, Chlebeck PJ, Van Amersfoort ES and Fernandez LA: Complement inhibition attenuates acute kidney injury after ischemia-reperfusion and limits progression to renal fibrosis in mice. PLoS One. 12(e0183701)2017.PubMed/NCBI View Article : Google Scholar
24	Qin H, Chen GX, Liang MY, Rong J, Yao JP, Liu H and Wu ZK: The altered expression profile of microRNAs in cardiopulmonary bypass canine models and the effects of mir-499 on myocardial ischemic reperfusion injury. J Transl Med. 11(154)2013.PubMed/NCBI View Article : Google Scholar
25	Hill JH and Ward PA: The phlogistic role of C3 leukotactic fragments in myocardial infarcts of rats. J Exp Med. 133:885–900. 1971.PubMed/NCBI View Article : Google Scholar
26	Yasojima K, Kilgore KS, Washington RA, Lucchesi BR and McGeer PL: Complement gene expression by rabbit heart: Upregulation by ischemia and reperfusion. Circ Res. 82:1224–1230. 1998.PubMed/NCBI View Article : Google Scholar
27	Kassimatis T, Qasem A, Douiri A, Ryan EG, Rebollo-Mesa I, Nichols LL, Greenlaw R, Olsburgh J, Smith RA, Sacks SH and Drage M: A double-blind randomised controlled investigation into the efficacy of Mirococept (APT070) for preventing ischaemia reperfusion injury in the kidney allograft (EMPIRIKAL): Study protocol for a randomised controlled trial. Trials. 18(255)2017.PubMed/NCBI View Article : Google Scholar
28	Vo AA, Zeevi A, Choi J, Cisneros K, Toyoda M, Kahwaji J, Peng A, Villicana R, Puliyanda D, Reinsmoen N, et al: A phase I/II placebo-controlled trial of C1-inhibitor for prevention of antibody-mediated rejection in HLA sensitized patients. Transplantation. 99:299–308. 2015.PubMed/NCBI View Article : Google Scholar
29	Thielmann M, Marggraf G, Neuhäuser M, Forkel J, Herold U, Kamler M, Massoudy P and Jakob H: Administration of C1-esterase inhibitor during emergency coronary artery bypass surgery in acute ST-elevation myocardial infarction. Eur J Cardiothorac Surg. 30:285–293. 2006.PubMed/NCBI View Article : Google Scholar
30	Smith PK, Carrier M, Chen JC, Haverich A, Levy JH, Menasché P, Shernan SK, Van de Werf F, Adams PX, Todaro TG and Verrier E: Effect of pexelizumab in coronary artery bypass graft surgery with extended aortic cross-clamp time. Ann Thorac Surg. 82:781–789. 2006.PubMed/NCBI View Article : Google Scholar
31	Tanhehco EJ, Yasojima K, McGeer PL, McGeer EG and Lucchesi BR: Preconditioning reduces myocardial complement gene expression in vivo. Am J Physiol Heart Circ Physiol. 279:H1157–H1165. 2000.PubMed/NCBI View Article : Google Scholar
32	Blancke F, Claeys MJ, Jorens P, Vermeiren G, Bosmans J, Wuyts FL and Vrints CJ: Systemic inflammation and reperfusion injury in patients with acute myocardial infarction. Mediators Inflamm. 2005:385–389. 2005.PubMed/NCBI View Article : Google Scholar
33	Kong Y, Rogers MR and Qin X: Effective neuroprotection by ischemic postconditioning is associated with a decreased expression of RGMa and inflammation mediators in ischemic rats. Neurochem Res. 38:815–825. 2013.PubMed/NCBI View Article : Google Scholar
34	Wu H, Lei S, Yuan J, Liu X, Zhang D, Gu X, Zhang L and Xia Z: Ischemic postconditioning downregulates Egr-1 expression and attenuates postischemic pulmonary inflammatory cytokine release and tissue injury in rats. J Surg Res. 181:204–212. 2013.PubMed/NCBI View Article : Google Scholar
35	Chen H, Wang L, Xing BZ, Liu XH, Chen ZY, Weng XD, Qiu T and Liu L: Ischemic postconditioning attenuates inflammation in rats following renal ischemia and reperfusion injury. Exp Ther Med. 10:513–518. 2015.PubMed/NCBI View Article : Google Scholar
36	Chen R, Zeng Z, Zhang YY, Cao C, Liu HM, Li W, Wu Y, Xia ZY, Ma D and Meng QT: Ischemic postconditioning attenuates acute kidney injury following intestinal ischemia-reperfusion through Nrf2-regulated autophagy, anti-oxidation, and anti-inflammation in mice. FASEB J. 34:8887–8901. 2020.PubMed/NCBI View Article : Google Scholar
37	Guo Q, Du X, Zhao Y, Zhang D, Yue L and Wang Z: Ischemic postconditioning prevents renal ischemia reperfusion injury through the induction of heat shock proteins in rats. Mol Med Rep. 10:2875–2881. 2014.PubMed/NCBI View Article : Google Scholar
38	Lin Z, Lin H, Li W, Huang Y and Dai H: Complement component C3 promotes cerebral ischemia/reperfusion injury mediated by TLR2/NFκB activation in diabetic mice. Neurochem Res. 43:1599–1607. 2018.PubMed/NCBI View Article : Google Scholar
39	Peng Q, Li K, Smyth LA, Xing G, Wang N, Meader L, Lu B, Sacks SH and Zhou W: C3a and C5a promote renal ischemia-reperfusion injury. J Am Soc Nephrol. 23:1474–1485. 2012.PubMed/NCBI View Article : Google Scholar
40	Gorsuch WB, Chrysanthou E, Schwaeble WJ and Stahl GL: The complement system in ischemia-reperfusion injuries. Immunobiology. 217:1026–1033. 2012.PubMed/NCBI View Article : Google Scholar
41	Liu M, Wang H, Zhang J, Yang X, Li B, Wu C and Zhu Q: NF-κB signaling pathway-enhanced complement activation mediates renal injury in trichloroethylene-sensitized mice. J Immunotoxicol. 15:63–72. 2018.PubMed/NCBI View Article : Google Scholar
42	Liu T, Zhang L, Joo D and Sun SC: NF-κB signaling in inflammation. Signal Transduct Target Ther. 2(17023)2017.PubMed/NCBI View Article : Google Scholar
43	Kin H, Wang NP, Mykytenko J, Reeves J, Deneve J, Jiang R, Zatta AJ, Guyton RA, Vinten-Johansen J and Zhao ZQ: Inhibition of myocardial apoptosis by postconditioning is associated with attenuation of oxidative stress-mediated nuclear factor-kappa B translocation and TNF alpha release. Shock. 29:761–768. 2008.PubMed/NCBI View Article : Google Scholar
44	Adachi T, Nakanishi M, Otsuka Y, Nishimura K, Hirokawa G, Goto Y, Nonogi H and Iwai N: Plasma microRNA 499 as a biomarker of acute myocardial infarction. Clin Chem. 56:1183–1185. 2010.PubMed/NCBI View Article : Google Scholar
45	Sluijter JP, van Mil A, van Vliet P, Metz CH, Liu J, Doevendans PA and Goumans MJ: MicroRNA-1 and -499 regulate differentiation and proliferation in human-derived cardiomyocyte progenitor cells. Arterioscler Thromb Vasc Biol. 30:859–868. 2010.PubMed/NCBI View Article : Google Scholar
46	Yang Z, Zhou Q, Fang Z, Yu L, Zhou J and Zhao B: Ischemic postconditioning improves longitudinal contractile function of the reperfused myocardium in patients with anterior wall acute myocardial infarction. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 44:1397–1405. 2019.PubMed/NCBI View Article : Google Scholar : (In Chinese).