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Berberine reduces ischemia/reperfusion-induced myocardial apoptosis via activating AMPK and PI3K–Akt signaling in diabetic rats

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Abstract

Diabetes increases the risk of cardiovascular diseases. Berberine (BBR), an isoquinoline alkaloid used in Chinese medicine, exerts anti-diabetic effect by lowering blood glucose and regulating lipid metabolism. It has been reported that BBR decreases mortality in patients with chronic congestive heart failure. However, the molecular mechanisms of these beneficial effects are incompletely understood. In the present study, we sought to determine whether BBR exerts cardioprotective effect against ischemia/reperfusion (I/R) injury in diabetic rats and the underlying mechanisms. Male Sprague-Dawley rats were injected with low dose streptozotocin and fed with a high-fat diet for 12 weeks to induce diabetes. The diabetic rats were intragastrically administered with saline or BBR (100, 200 and 400 mg/kg/d) starting from week 9 to 12. At the end of week 12, all rats were subjected to 30 min of myocardial ischemia and 3 h of reperfusion. BBR significantly improved the recovery of cardiac systolic/diastolic function and reduced myocardial apoptosis in diabetic rats subjected to myocardial I/R. Furthermore, in cultured neonatal rat cardiomyocytes, BBR (50 μmol/L) reduced hypoxia/reoxygenation-induced myocardial apoptosis, increased Bcl-2/Bax ratio and decreased caspase-3 expression, together with enhanced activation of PI3K–Akt and increased adenosine monophosphate-activated protein kinase (AMPK) and eNOS phosphorylation. Pretreatment with either PI3K/Akt inhibitor wortmannin or AMPK inhibitor Compound C blunted the anti-apoptotic effect of BBR. Our findings demonstrate that BBR exerts anti-apoptotic effect and improves cardiac functional recovery following myocardial I/R via activating AMPK and PI3K–Akt–eNOS signaling in diabetic rats.

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References

  1. Yang W, Lu J, Weng J, Jia W, Ji L, Xiao J et al (2010) Prevalence of diabetes among men and women in China. N Engl J Med 362:1090–1101

    Article  CAS  PubMed  Google Scholar 

  2. Xie N, Zhang W, Li J, Liang H, Zhou H, Duan W et al (2011) α-Linolenic acid intake attenuates myocardial ischemia/reperfusion injury through anti-inflammatory and anti-oxidative stress effects in diabetic but not normal rats. Arch Med Res 42:171–181

    Article  CAS  PubMed  Google Scholar 

  3. Thom T, Haase N, Rosamond W, Howard VJ, Rumsfeld J, Manolio T et al (2006) Heart disease and stroke statistics—2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 113:e85–e151

    Article  PubMed  Google Scholar 

  4. Woodfield SL, Lundergan CF, Reiner JS, Greenhouse SW, Thompson MA, Rohrbeck SC et al (1996) Angiographic findings and outcome in diabetic patients treated with thrombolytic therapy for acute myocardial infarction: the GUSTO-I experience. J Am Coll Cardiol 28:1661–1669

    Article  CAS  PubMed  Google Scholar 

  5. Lee MG, Jeong MH, Ahn Y, Chae SC, Hur SH, Hong TJ et al (2009) Comparison of clinical outcomes following acute myocardial infarctions in hypertensive patients with or without diabetes. Korean Circ J 39:243–250

    Article  PubMed Central  PubMed  Google Scholar 

  6. Zhang Y, Wei L, Sun D, Cao F, Gao H, Zhao L et al (2010) Tanshinone IIA pretreatment protects myocardium against ischaemia/reperfusion injury through the phosphatidylinositol 3-kinase/Akt-dependent pathway in diabetic rats. Diabetes Obes Metab 12:316–322

    Article  CAS  PubMed  Google Scholar 

  7. Lekli I, Szabo G, Juhasz B, Das S, Das M, Varga E et al (2008) Protective mechanisms of resveratrol against ischemia-reperfusion-induced damage in hearts obtained from Zucker obese rats: the role of GLUT-4 and endothelin. Am J Physiol Heart Circ Physiol 294:H859–H866

    Article  CAS  PubMed  Google Scholar 

  8. Chu LM, Osipov RM, Robich MP, Feng J, Sheller MR, Sellke FW (2010) Effect of thrombin fragment (TP508) on myocardial ischemia reperfusion injury in a model of type 1 diabetes mellitus. Circulation 122:S162–S169

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Dong H, Wang N, Zhao L, Lu F (2012) Berberine in the treatment of type 2 diabetes mellitus: a systemic review and meta-analysis. Evid Based Complement Alternat Med 2012:591654

    Article  PubMed Central  PubMed  Google Scholar 

  10. Chueh WH, Lin JY (2011) Berberine, an isoquinoline alkaloid in herbal plants, protects pancreatic islets and serum lipids in nonobese diabetic mice. J Agric Food Chem 59:8021–8027

    Article  CAS  PubMed  Google Scholar 

  11. Dong SF, Hong Y, Liu M, Hao YZ, Yu HS, Liu Y et al (2011) Berberine attenuates cardiac dysfunction in hyperglycemic and hypercholesterolemic rats. Eur J Pharmacol 660:368–374

    Article  CAS  PubMed  Google Scholar 

  12. Wang Y, Huang Y, Lam KS, Li Y, Wong WT, Ye H et al (2009) Berberine prevents hyperglycemia-induced endothelial injury and enhances vasodilatation via adenosine monophosphate-activated protein kinase and endothelial nitric oxide synthase. Cardiovasc Res 82:484–492

    Article  CAS  PubMed  Google Scholar 

  13. Zhang H, Wei J, Xue R, Wu JD, Zhao W, Wang ZZ et al (2010) Berberine lowers blood glucose in type 2 diabetes mellitus patients through increasing insulin receptor expression. Metabolism 59:285–292

    Article  PubMed  Google Scholar 

  14. Zhou L, Yang Y, Wang X, Liu S, Shang W, Yuan G et al (2007) Berberine stimulates glucose transport through a mechanism distinct from insulin. Metabolism 56:405–412

    Article  CAS  PubMed  Google Scholar 

  15. Zhang Y, Li X, Zou D, Liu W, Yang J, Zhu N et al (2008) Treatment of type 2 diabetes and dyslipidemia with the natural plant alkaloid berberine. J Clin Endocrinol Metab 93:2559–2565

    Article  CAS  PubMed  Google Scholar 

  16. Turner N, Li JY, Gosby A, To SW, Cheng Z, Miyoshi H et al (2008) Berberine and its more biologically available derivative, dihydroberberine, inhibit mitochondrial respiratory complex I: a mechanism for the action of berberine to activate AMP-activated protein kinase and improve insulin action. Diabetes 57:1414–1418

    Article  CAS  PubMed  Google Scholar 

  17. Yin J, Gao Z, Liu D, Liu Z, Ye J (2008) Berberine improves glucose metabolism through induction of glycolysis. Am J Physiol Endocrinol Metab 294:E148–E156

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Lee YS, Kim WS, Kim KH, Yoon MJ, Cho HJ, Shen Y et al (2006) Berberine, a natural plant product, activates AMP-activated protein kinase with beneficial metabolic effects in diabetic and insulin-resistant states. Diabetes 55:2256–2264

    Article  CAS  PubMed  Google Scholar 

  19. Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C et al (2004) Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med 10:1344–1351

    Article  CAS  PubMed  Google Scholar 

  20. Wang C, Li J, Lv X, Zhang M, Song Y, Chen L et al (2009) Ameliorative effect of berberine on endothelial dysfunction in diabetic rats induced by high-fat diet and streptozotocin. Eur J Pharmacol 620:131–137

    Article  CAS  PubMed  Google Scholar 

  21. Cui G, Qin X, Zhang Y, Gong Z, Ge B, Zang YQ (2009) Berberine differentially modulates the activities of ERK, p38 MAPK, and JNK to suppress Th17 and Th1 T cell differentiation in type 1 diabetic mice. J Biol Chem 284:28420–28429

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Ko BS, Choi SB, Park SK, Jang JS, Kim YE, Park S (2005) Insulin sensitizing and insulinotropic action of berberine from Cortidis rhizoma. Biol Pharm Bull 28:1431–1437

    Article  CAS  PubMed  Google Scholar 

  23. Yin J, Hu R, Chen M, Tang J, Li F, Yang Y et al (2002) Effects of berberine on glucose metabolism in vitro. Metabolism 51:1439–1443

    Article  CAS  PubMed  Google Scholar 

  24. Zhang KR, Liu HT, Zhang HF, Zhang QJ, Li QX, Yu QJ et al (2007) Long-term aerobic exercise protects the heart against ischemia/reperfusion injury via PI3 kinase-dependent and Akt-mediated mechanism. Apoptosis 12:1579–1588

    Article  CAS  PubMed  Google Scholar 

  25. Yue TL, Wang C, Gu JL, Ma XL, Kumar S, Lee JC et al (2000) Inhibition of extracellular signal-regulated kinase enhances Ischemia/Reoxygenation-induced apoptosis in cultured cardiac myocytes and exaggerates reperfusion injury in isolated perfused heart. Circ Res 86:692–699

    Article  CAS  PubMed  Google Scholar 

  26. Ma YG, Dong L, Ye XL, Deng CL, Cheng JH, Liu WC et al (2010) Activation of cloned BK(Ca) channels in nitric oxide-induced apoptosis of HEK293 cells. Apoptosis 15:426–438

    Article  CAS  PubMed  Google Scholar 

  27. Xing W, Yan W, Fu F, Jin Y, Ji L, Liu W et al (2009) Insulin inhibits myocardial ischemia-induced apoptosis and alleviates chronic adverse changes in post-ischemic cardiac structure and function. Apoptosis 14:1050–1060

    Article  CAS  PubMed  Google Scholar 

  28. Li J, Zhang H, Wu F, Nan Y, Ma H, Guo W et al (2008) Insulin inhibits tumor necrosis factor-alpha induction in myocardial ischemia/reperfusion: role of Akt and endothelial nitric oxide synthase phosphorylation. Crit Care Med 36:1551–1558

    Article  CAS  PubMed  Google Scholar 

  29. Ma H, Zhang HF, Yu L, Zhang QJ, Li J, Huo JH et al (2006) Vasculoprotective effect of insulin in the ischemic/reperfused canine heart: role of Akt-stimulated NO production. Cardiovasc Res 69:57–65

    Article  CAS  PubMed  Google Scholar 

  30. Saraste A, Pulkki K, Kallajoki M, Henriksen K, Parvinen M, Voipio-Pulkki LM (1997) Apoptosis in human acute myocardial infarction. Circulation 95:320–323

    Article  CAS  PubMed  Google Scholar 

  31. Ohno M, Takemura G, Ohno A, Misao J, Hayakawa Y, Minatoguchi S et al (1998) “Apoptotic” myocytes in infarct area in rabbit hearts may be oncotic myocytes with DNA fragmentation: analysis by immunogold electron microscopy combined with In situ nick end-labeling. Circulation 98:1422–1430

    Article  CAS  PubMed  Google Scholar 

  32. Gao F, Gao E, Yue TL, Ohlstein EH, Lopez BL, Christopher TA et al (2002) Nitric oxide mediates the antiapoptotic effect of insulin in myocardial ischemia-reperfusion: the roles of PI3-kinase, Akt, and endothelial nitric oxide synthase phosphorylation. Circulation 105:1497–1502

    Article  CAS  PubMed  Google Scholar 

  33. Misao J, Hayakawa Y, Ohno M, Kato S, Fujiwara T, Fujiwara H (1996) Expression of bcl-2 protein, an inhibitor of apoptosis, and Bax, an accelerator of apoptosis, in ventricular myocytes of human hearts with myocardial infarction. Circulation 94:1506–1512

    Article  CAS  PubMed  Google Scholar 

  34. Nishikawa S, Tatsumi T, Shiraishi J, Matsunaga S, Takeda M, Mano A et al (2006) Nicorandil regulates Bcl-2 family proteins and protects cardiac myocytes against hypoxia-induced apoptosis. J Mol Cell Cardiol 40:510–519

    Article  CAS  PubMed  Google Scholar 

  35. Zeng XH, Zeng XJ, Li YY (2003) Efficacy and safety of berberine for congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 92:173–176

    Article  CAS  PubMed  Google Scholar 

  36. Guo Y, Pope C, Cheng X, Zhou H, Klaassen CD (2011) Dose-response of berberine on hepatic cytochromes P450 mRNA expression and activities in mice. J Ethnopharmacol 138:111–118

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Seubert J, Yang B, Bradbury JA, Graves J, Degraff LM, Gabel S et al (2004) Enhanced postischemic functional recovery in CYP2J2 transgenic hearts involves mitochondrial ATP-sensitive K + channels and p42/p44 MAPK pathway. Circ Res 95:506–514

    Article  CAS  PubMed  Google Scholar 

  38. Fu J, Huang H, Liu J, Pi R, Chen J, Liu P (2007) Tanshinone IIA protects cardiac myocytes against oxidative stress-triggered damage and apoptosis. Eur J Pharmacol 568:213–221

    Article  CAS  PubMed  Google Scholar 

  39. Song JQ, Teng X, Cai Y, Tang CS, Qi YF (2009) Activation of Akt/GSK-3beta signaling pathway is involved in intermedin(1-53) protection against myocardial apoptosis induced by ischemia/reperfusion. Apoptosis 14:1061–1069

    Article  CAS  PubMed  Google Scholar 

  40. Yu W, Sheng M, Xu R, Yu J, Cui K, Tong J et al (2013) Berberine protects human renal proximal tubular cells from hypoxia/reoxygenation injury via inhibiting endoplasmic reticulum and mitochondrial stress pathways. J Transl Med 11:24

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Gao F, Tao L, Yan W, Gao E, Liu HR, Lopez BL et al (2004) Early anti-apoptosis treatment reduces myocardial infarct size after a prolonged reperfusion. Apoptosis 9:553–559

    Article  CAS  PubMed  Google Scholar 

  42. Miller EJ, Li J, Leng L, McDonald C, Atsumi T, Bucala R et al (2008) Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart. Nature 451:578–582

    Article  CAS  PubMed  Google Scholar 

  43. Ma H, Wang J, Thomas DP, Tong C, Leng L, Wang W et al (2010) Impaired macrophage migration inhibitory factor-AMP-activated protein kinase activation and ischemic recovery in the senescent heart. Circulation 122:282–292

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  44. Russell RR, Li J, Coven DL, Pypaert M, Zechner C, Palmeri M et al (2004) AMP-activated protein kinase mediates ischemic glucose uptake and prevents postischemic cardiac dysfunction, apoptosis, and injury. J Clin Invest 114:495–503

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Stein SC, Woods A, Jones NA, Davison MD, Carling D (2000) The regulation of AMP-activated protein kinase by phosphorylation. Biochem J 345(Pt 3):437–443

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Zhang W, Wang R, Han SF, Bu L, Wang SW, Ma H et al (2007) Alpha-linolenic acid attenuates high glucose-induced apoptosis in cultured human umbilical vein endothelial cells via PI3K/Akt/eNOS pathway. Nutrition 23:762–770

    Article  CAS  PubMed  Google Scholar 

  47. Ansley DM, Wang B (2013) Oxidative stress and myocardial injury in the diabetic heart. J Pathol 229:232–241

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  48. Boo YC, Sorescu G, Boyd N, Shiojima I, Walsh K, Du J et al (2002) Shear stress stimulates phosphorylation of endothelial nitric-oxide synthase at Ser1179 by Akt-independent mechanisms: role of protein kinase A. J Biol Chem 277:3388–3396

    Article  CAS  PubMed  Google Scholar 

  49. Zhang Y, Lee TS, Kolb EM, Sun K, Lu X, Sladek FM et al (2006) AMP-activated protein kinase is involved in endothelial NO synthase activation in response to shear stress. Arterioscler Thromb Vasc Biol 26:1281–1287

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by the State Key Program of National Natural Science Foundation of China (No. 81030005) and grants from the National Nature Science Foundation of China (Nos. 30800432, 81270301), Traditional Chinese Medicine Foundation of Shaanxi Province (No. JC38) and National Science and Technology Major Project (No. 2009ZX09301-009).

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Physiology, The Fourth Military Medical University, Xi’an, 710032, China

    Keke Chen, Guohua Li, Fenghao Geng, Zhao Zhang, Jiani Li, Min Yang, Ling Dong & Feng Gao

  2. School of Biological Technology, Xi’an University of Arts and Science, Xi’an, 710065, China

    Keke Chen

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  1. Keke Chen
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  2. Guohua Li
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  4. Zhao Zhang
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  7. Ling Dong
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Correspondence to Ling Dong or Feng Gao.

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Keke Chen and Guohua Li contributed equally to this study.

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Chen, K., Li, G., Geng, F. et al. Berberine reduces ischemia/reperfusion-induced myocardial apoptosis via activating AMPK and PI3K–Akt signaling in diabetic rats. Apoptosis 19, 946–957 (2014). https://doi.org/10.1007/s10495-014-0977-0

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