远端缺血后适应通过抑制RAGE的表达实现对心肌的保护作用
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摘要
目的:探讨晚期糖基化终末产物受体(receptor for advanced glycation end products,RAGE)在远端缺血后适应改善心肌缺血再灌注中的作用。方法:将34只8～9周龄C57BL/6J小鼠随机分为6组:假手术组(Sham组)、FPS-ZM1对照组(FZM1组)、缺血再灌注组(IR组)、FPS-ZM1干预组(FZM1+IR组)、远端缺血后适应组(RIPostC+IR组)和FZM1+远端缺血后适应干预组(FZM1+RIPostC+IR组)。通过结扎左冠状动脉,建立小鼠心肌缺血再灌注模型。采用小鼠心超仪检测小鼠左室射血分数(left ventricular ejection fraction,LVEF)和左室缩短分数(left ventricular fractional shortening,LVFS),运用酶联免疫分析(ELISA)法和蛋白印迹法检测炎症因子白介素6(interleukin 6,IL-6)、核因子(nudear factor,NF)-κB P65蛋白、RAGE蛋白。结果:①与IR组相比,RIPostC能显著增加LVEF(P <0.01)和LVFS(P <0.01)。②与IR组相比,RIPostC能显著降低RAGE(P <0.001)的表达。③与IR组相比,RIPostC能显著减少NF-κB P65(P <0.001)和IL-6(P <0.001)的表达。结论:RIPostC对心肌缺血再灌注损伤具有保护作用。该作用可能通过抑制RAGE的表达进而降低炎性反应而实现。
Objective:This study aimed to investigate the role of receptor for advanced glycation end products(RAGE)in improving myocardial ischemia and reperfusion after remote ischemic postconditioning. Methods:Thirty-four C57/B6 mice aged 8-9 weeks were randomly divided into six groups:the sham operation group(sham),the FPS-ZM1 control group(FZM1),the ischemia and resperfusion group(IR),the FPS-ZM1 intervention group(FZM1+IR),the RIPostC group(RIPostC+IR)and the RIPostC intervention group(RIPostC+FZM1+IR). The anterior descending coronary artery was ligated to create myocardial ischemia-reperfusion model of mouse.The left ventricular ejection fraction(LVEF)and left ventricular shortening fraction(LVFS)of mice were detected by mouse cardiac ultrasonography,and the inflammatory factor IL - 6,NF - κB P65 protein and RAGE protein were detected by enzyme - linked immunoassay(ELISA)and Western blotting. Results:①RIPostC significantly increased LVEF(P < 0.01)and LVFS(P < 0.01)compared with the I/R group. ②Compared with the IR group,RIPostC significantly reduced the expression of RAGE(P < 0.001). ③RIPostC significantly reduced the expression of NF - κB P65(P < 0.001)and IL - 6(P < 0.001)compared with the I/R group.Conclusion:RIPostC was effective in protecting against myocardial ischemia - reperfusion injury. The cardioprotective effects of RIPostC may be achieved directly by inhibiting the expression of RAGE and thereby reducing the inflammatory response.
Objective:This study aimed to investigate the role of receptor for advanced glycation end products(RAGE)in improving myocardial ischemia and reperfusion after remote ischemic postconditioning. Methods:Thirty-four C57/B6 mice aged 8-9 weeks were randomly divided into six groups:the sham operation group(sham),the FPS-ZM1 control group(FZM1),the ischemia and resperfusion group(IR),the FPS-ZM1 intervention group(FZM1+IR),the RIPostC group(RIPostC+IR)and the RIPostC intervention group(RIPostC+FZM1+IR). The anterior descending coronary artery was ligated to create myocardial ischemia-reperfusion model of mouse.The left ventricular ejection fraction(LVEF)and left ventricular shortening fraction(LVFS)of mice were detected by mouse cardiac ultrasonography,and the inflammatory factor IL - 6,NF - κB P65 protein and RAGE protein were detected by enzyme - linked immunoassay(ELISA)and Western blotting. Results:①RIPostC significantly increased LVEF(P < 0.01)and LVFS(P < 0.01)compared with the I/R group. ②Compared with the IR group,RIPostC significantly reduced the expression of RAGE(P < 0.001). ③RIPostC significantly reduced the expression of NF - κB P65(P < 0.001)and IL - 6(P < 0.001)compared with the I/R group.Conclusion:RIPostC was effective in protecting against myocardial ischemia - reperfusion injury. The cardioprotective effects of RIPostC may be achieved directly by inhibiting the expression of RAGE and thereby reducing the inflammatory response.
引文
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[2] Niemann B,Schwarzer M,Rohrbach S. Heart and mito-chondria:pathophysiology and implications for cardiac surgeons[J]. Thorac Cardiovasc Surg,2018,66(1):11-19
[3] Suchal K,Bhatia J,Malik S,et al. Seabuckthorn pulp oil protects against myocardial ischemia-reperfusion injury in rats through activation of Akt/eNOS[J]. Front Pharma-col,2016,7:155
[4] Wang X,Wang J,Tu T,et al. Remote ischemic postcondi-tioning protects against myocardial ischemia-reperfusion injury by inhibition of the RAGE-HMGB1 pathway[J].Biomed Res Int,2018,2018:4565630
[5] Murry CE,Jennings RB,Reimer KA. Preconditioning with ischemia:a delay of lethal cell injury in ischemic myocar-dium[J]. Circulation,1986,74(5):1124-1136
[6] Kerendi F,Kin H,Halkos ME,et al. Remote postcondi-tioning. Brief renal ischemia and reperfusion applied be-fore coronary artery reperfusion reduces myocardial in-farct size via endogenous activation of adenosine receptors[J]. Basic Res Cardiol,2005,100(5):404-412
[7] Aimo A,Borrelli C,Giannoni A,et al. Cardioprotection by remote ischemic conditioning:Mechanisms and clinical evidences[J]. World J Cardiol,2015,7(10):621-632
[8] Boengler K,Lochnit G,Schulz R. Mitochondria“THE”target of myocardial conditioning[J]. Am J Physiol Heart Circ Physiol,2018,315(5):H1215-H1231
[9] Mewton N,Ivanes F,Cour M,et al. Postconditioning:from experimental proof to clinical concept[J]. Dis Model Mech,2010,3(1-2):39-44
[10] Nogueira-Machado JA,de Oliveira Volpe CM. HMGB-1as a target for inflammation controlling[J]. Recent Pat En-docr Metab Immune Drug Discov,2012,6(3):201-209
[11] Wu X,Gu W,Lu H,et al. Soluble receptor for advanced glycation end product ameliorates chronic intermittent Hy-poxia induced renal injury,inflammation,and apoptosis via P38/JNK signaling pathways[J]. Oxid Med Cell Lon-gev,2016,2016:1015390
[12]Aleshin A,Ananthakrishnan R,Li Q,et al. RAGE modu-lates myocardial injury consequent to LAD infarction via impact on JNK and STAT signaling in a murine model[J].Am J Physiol Heart Circ Physiol,2008,294(4):H1823-H1832
[13] Shang L,Ananthakrishnan R,Li Q,et al. RAGE modu-lates hypoxia/reoxygenation injury in adult murine cardio-myocytes via JNK and GSK-3beta signaling pathways[J].PLoS One,2010,5(4):e10092
[14] Steffens S,Montecucco F,Mach F. The inflammatory re-sponse as a target to reduce myocardial ischaemia and re-perfusion injury[J]. Thromb Haemost,2009,102(2):240-247
[15]Chandrasekar B,Freeman GL. Induction of nuclear factor kappaB and activation protein 1 in postischemic myocardi-um[J]. FEBS Lett,1997,401(1):30-34
[16] Li C,Gao Y,Tian J,et al. Sophocarpine administration preserves myocardial function from ischemia-reperfusion in rats via NF-kappaB inactivation[j]. J Ethnopharmacol,2011,135(3):620-625
[17]Cain BS,Meldrum DR,Dinarello CA,et al. Tumor necro-sis factor-alpha and interleukin-1beta synergistically de-press human myocardial function[J]. Crit Care Med,1999,27(7):1309-1318
[18] Kimura H,Shintani-Ishida K,Nakajima M,et al. Ischemic preconditioning or p38 MAP kinase inhibition attenuates myocardial TNF alpha production and mitochondria dam-age in brief myocardial ischemia[J]. Life Sci,2006,78(17):1901-1910