Naringin inhibits high glucose-induced cardiomyocyte apoptosis by attenuating mitochondrial dysfunction and modulating the activation of the p38 signaling pathway

Huang,Haili; Wu,Keng; You,Qiong; Huang,Ruina; Li,Shanghai; Wu,Keng

doi:10.3892/ijmm.2013.1403

Naringin inhibits high glucose-induced cardiomyocyte apoptosis by attenuating mitochondrial dysfunction and modulating the activation of the p38 signaling pathway

Authors:
- Haili Huang
- Keng Wu
- Qiong You
- Ruina Huang
- Shanghai Li
View Affiliations

Affiliations: Clinical Research Center, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China, Department of Cardiology, Affiliated Hospital of Guangdong Medical College, Zhanjiang, Guangdong 524001, P.R. China
Published online on: June 3, 2013 https://doi.org/10.3892/ijmm.2013.1403
Pages: 396-402

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

Recently, naringin (NAR; 4',5,7-trihydroxyflavanone-7-rhamnoglucoside) has been shown to have cardioprotective properties. However, the specific mechanisms underlying its cardioprotective effects remain unclear. In this study, we aimed to investigate the cardioprotective effects of NAR and the possible underlying molecular mechanisms in cardiomyocytes using high glucose (HG) to induce apoptosis in H9c2 cells. The effect of NAR on apoptosis was assessed by Annexin V and propidium iodide staining, and by determining the levels of active caspase-3, -8 and -9. The effect of NAR on mitochondrial dysfunction was assessed by the loss of mitochondrial membrane potential (MMP). Our results demonstrated that exposure to HG induced apoptosis and mitochondrial dysfunction in cardiomyocytes. Treatment with NAR significantly increased MMP and inhibited the activation of caspase-3, -8 and -9. NAR attenuated the HG-induced p38 and p53 phosphorylation, decreased mitochondrial Bax and Bak expression, prevented the release of cytochrome c and increased Bcl-2 expression. Pre-treatment with SB203580, a p38 inhibitor, also suppressed p53 phosphorylation and prevented the loss of MMP, as well as apoptosis in the HG-treated H9c2 cells. Taken together, these data demonstrate that NAR inhibits HG-induced apoptosis by attenuating mitochondrial dysfunction and modulating the activation of the p38 signaling pathway.

View Figures

View References

1	Cai L and Kang YJ: Cell death and diabetic cardiomyopathy. Cardiovasc Toxicol. 3:219–228. 2003. View Article : Google Scholar
2	Adeghate E: Molecular and cellular basis of the aetiology and management of diabetic cardiomyopathy: a short review. Mol Cell Biochem. 261:187–191. 2004. View Article : Google Scholar : PubMed/NCBI
3	Lakshmanan AP, Harima M, Suzuki K, et al: The hyperglycemia stimulated myocardial endoplasmic reticulum (ER) stress contributes to diabetic cardiomyopathy in the transgenic non-obese type 2 diabetic rats: a differential role of unfolded protein response (UPR) signaling proteins. Int J Biochem Cell Biol. 45:438–447. 2013. View Article : Google Scholar
4	Jankyova S, Kmecova J, Cernecka H, et al: Glucose and blood pressure lowering effects of Pycnogenol^® are inefficient to prevent prolongation of QT interval in experimental diabetic cardiomyopathy. Pathol Res Pract. 208:452–457. 2012. View Article : Google Scholar : PubMed/NCBI
5	Cai L: Diabetic cardiomyopathy and its prevention by metallothionein: experimental evidence, possible mechanisms and clinical implications. Curr Med Chem. 14:2193–2203. 2007. View Article : Google Scholar
6	Miki T, Yuda S, Kouzu H and Miura T: Diabetic cardiomyopathy: pathophysiology and clinical features. Heart Fail Rev. Mar 28–2012.(Epub ahead of print).
7	Regan TJ, Ahmed S, Haider B, Moschos C and Weisse A: Diabetic cardiomyopathy: experimental and clinical observations. N J Med. 91:776–778. 1994.PubMed/NCBI
8	Frustaci A, Kajstura J, Chimenti C, et al: Myocardial cell death in human diabetes. Circ Res. 87:1123–1132. 2000. View Article : Google Scholar
9	Cai L, Wang Y, Zhou G, et al: Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy. J Am Coll Cardiol. 48:1688–1697. 2006. View Article : Google Scholar : PubMed/NCBI
10	Green DR and Reed JC: Mitochondria and apoptosis. Science. 281:1309–1312. 1998. View Article : Google Scholar : PubMed/NCBI
11	Condorelli G, Morisco C, Stassi G, et al: Increased cardiomyocyte apoptosis and changes in proapoptotic and antiapoptotic genes bax and bcl-2 during left ventricular adaptations to chronic pressure overload in the rat. Circulation. 99:3071–3078. 1999. View Article : Google Scholar : PubMed/NCBI
12	Lv X, Yu X, Wang Y, et al: Berberine inhibits doxorubicin-triggered cardiomyocyte apoptosis via attenuating mitochondrial dysfunction and increasing Bcl-2 expression. PLoS One. 7:e473512012. View Article : Google Scholar
13	Ruffolo SC and Shore GC: BCL-2 selectively interacts with the BID-induced open conformer of BAK, inhibiting BAK auto-oligomerization. J Biol Chem. 278:25039–25045. 2003. View Article : Google Scholar : PubMed/NCBI
14	Youle RJ and Strasser A: The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol. 9:47–59. 2008. View Article : Google Scholar : PubMed/NCBI
15	Yi X, Yin XM and Dong Z: Inhibition of Bid-induced apoptosis by Bcl-2. tBid insertion, Bax translocation, and Bax/Bak oligomerization suppressed. J Biol Chem. 278:16992–16999. 2003. View Article : Google Scholar : PubMed/NCBI
16	Kim SJ, Hwang SG, Shin DY, Kang SS and Chun JS: p38 kinase regulates nitric oxide-induced apoptosis of articular chondrocytes by accumulating p53 via NFkappa B-dependent transcription and stabilization by serine 15 phosphorylation. J Biol Chem. 277:33501–33508. 2002. View Article : Google Scholar
17	Jain M and Parmar HS: Evaluation of antioxidative and anti-inflammatory potential of hesperidin and naringin on the rat air pouch model of inflammation. Inflamm Res. 60:483–491. 2011. View Article : Google Scholar : PubMed/NCBI
18	Kawaguchi K, Maruyama H, Hasunuma R and Kumazawa Y: Suppression of inflammatory responses after onset of collagen-induced arthritis in mice by oral administration of the Citrus flavanone naringin. Immunopharmacol Immunotoxicol. 33:723–729. 2011. View Article : Google Scholar : PubMed/NCBI
19	Cavia-Saiz M, Busto MD, Pilar-Izquierdo MC, Ortega N, Perez-Mateos M and Muniz P: Antioxidant properties, radical scavenging activity and biomolecule protection capacity of flavonoid naringenin and its glycoside naringin: a comparative study. J Sci Food Agric. 90:1238–1244. 2010. View Article : Google Scholar
20	Jagetia GC and Reddy TK: Alleviation of iron induced oxidative stress by the grape fruit flavanone naringin in vitro. Chem Biol Interact. 190:121–128. 2011. View Article : Google Scholar : PubMed/NCBI
21	Camargo CA, Gomes-Marcondes MC, Wutzki NC and Aoyama H: Naringin inhibits tumor growth and reduces interleukin-6 and tumor necrosis factor alpha levels in rats with Walker 256 carcinosarcoma. Anticancer Res. 32:129–133. 2012.PubMed/NCBI
22	Celiz G, Daz M and Audisio MC: Antibacterial activity of naringin derivatives against pathogenic strains. J Appl Microbiol. 111:731–738. 2011. View Article : Google Scholar : PubMed/NCBI
23	Carino-Cortes R, Alvarez-Gonzalez I, Martino-Roaro L and Madrigal-Bujaidar E: Effect of naringin on the DNA damage induced by daunorubicin in mouse hepatocytes and cardiocytes. Biol Pharm Bull. 33:697–701. 2010. View Article : Google Scholar : PubMed/NCBI
24	Gao S, Li P, Yang H, Fang S and Su W: Antitussive effect of naringin on experimentally induced cough in Guinea pigs. Planta Med. 77:16–21. 2011. View Article : Google Scholar : PubMed/NCBI
25	Liu M, Zou W, Yang C, Peng W and Su W: Metabolism and excretion studies of oral administered naringin, a putative antitussive, in rats and dogs. Biopharm Drug Dispos. 33:123–134. 2012. View Article : Google Scholar : PubMed/NCBI
26	Gopinath K, Prakash D and Sudhandiran G: Neuroprotective effect of naringin, a dietary flavonoid against 3-nitropropionic acid-induced neuronal apoptosis. Neurochem Int. 59:1066–1073. 2011. View Article : Google Scholar : PubMed/NCBI
27	Gopinath K and Sudhandiran G: Naringin modulates oxidative stress and inflammation in 3-nitropropionic acid-induced neurodegeneration through the activation of nuclear factor-erythroid 2-related factor-2 signalling pathway. Neuroscience. 227:134–143. 2012. View Article : Google Scholar
28	Kandhare AD, Raygude KS, Ghosh P, Ghule AE and Bodhankar SL: Neuroprotective effect of naringin by modulation of endogenous biomarkers in streptozotocin induced painful diabetic neuropathy. Fitoterapia. 83:650–659. 2012. View Article : Google Scholar : PubMed/NCBI
29	Ikemura M, Sasaki Y, Giddings JC and Yamamoto J: Preventive effects of hesperidin, glucosyl hesperidin and naringin on hypertension and cerebral thrombosis in stroke-prone spontaneously hypertensive rats. Phytother Res. 26:1272–1277. 2012. View Article : Google Scholar : PubMed/NCBI
30	Chanet A, Milenkovic D, Deval C, et al: Naringin, the major grapefruit flavonoid, specifically affects atherosclerosis development in diet-induced hypercholesterolemia in mice. J Nutr Biochem. 23:469–477. 2012. View Article : Google Scholar
31	Kanno S, Shouji A, Asou K and Ishikawa M: Effects of naringin on hydrogen peroxide-induced cytotoxicity and apoptosis in P388 cells. J Pharmacol Sci. 92:166–170. 2003. View Article : Google Scholar : PubMed/NCBI
32	Kim HJ, Song JY, Park HJ, Park HK, Yun DH and Chung JH: Naringin protects against rotenone-induced apoptosis in human neuroblastoma SH-SY5Y cells. Korean J Physiol Pharmacol. 13:281–285. 2009. View Article : Google Scholar
33	Mahmoud AM, Ashour MB, Abdel-Moneim A and Ahmed OM: Hesperidin and naringin attenuate hyperglycemia-mediated oxidative stress and proinflammatory cytokine production in high fat fed/streptozotocin-induced type 2 diabetic rats. J Diabetes Complications. 26:483–490. 2012. View Article : Google Scholar
34	Ramesh E and Alshatwi AA: Naringin induces death receptor and mitochondria-mediated apoptosis in human cervical cancer (SiHa) cells. Food Chem Toxicol. 51:97–105. 2013. View Article : Google Scholar : PubMed/NCBI
35	Nie YC, Wu H, Li PB, et al: Anti-inflammatory effects of naringin in chronic pulmonary neutrophilic inflammation in cigarette smoke-exposed rats. J Med Food. 15:894–900. 2012. View Article : Google Scholar : PubMed/NCBI
36	Xulu S and Oroma Owira PM: Naringin ameliorates atherogenic dyslipidemia but not hyperglycemia in rats with type 1 diabetes. J Cardiovasc Pharmacol. 59:133–141. 2012. View Article : Google Scholar : PubMed/NCBI
37	Rajadurai M and Prince PS: Naringin ameliorates mitochondrial lipid peroxides, antioxidants and lipids in isoproterenol-induced myocardial infarction in Wistar rats. Phytother Res. 23:358–362. 2009. View Article : Google Scholar
38	Punithavathi VR, Anuthama R and Prince PS: Combined treatment with naringin and vitamin C ameliorates streptozotocin-induced diabetes in male Wistar rats. J Appl Toxicol. 28:806–813. 2008. View Article : Google Scholar : PubMed/NCBI
39	Shore GC and Nguyen M: Bcl-2 proteins and apoptosis: choose your partner. Cell. 135:1004–1006. 2008. View Article : Google Scholar : PubMed/NCBI
40	Cai L, Li W, Wang G, Guo L, Jiang Y and Kang YJ: Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes. 51:1938–1948. 2002. View Article : Google Scholar : PubMed/NCBI
41	Fiordaliso F, Leri A, Cesselli D, et al: Hyperglycemia activates p53 and p53-regulated genes leading to myocyte cell death. Diabetes. 50:2363–2375. 2001. View Article : Google Scholar : PubMed/NCBI
42	Miyashita T and Reed JC: Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell. 80:293–299. 1995. View Article : Google Scholar : PubMed/NCBI
43	Zhu W, Soonpaa MH, Chen H, et al: Acute doxorubicin cardiotoxicity is associated with p53-induced inhibition of the mammalian target of rapamycin pathway. Circulation. 119:99–106. 2009. View Article : Google Scholar : PubMed/NCBI
44	Childs AC, Phaneuf SL, Dirks AJ, Phillips T and Leeuwenburgh C: Doxorubicin treatment in vivo causes cytochrome C release and cardiomyocyte apoptosis, as well as increased mitochondrial efficiency, superoxide dismutase activity, and Bcl-2:Bax ratio. Cancer Res. 62:4592–4598. 2002.
45	Younce CW, Burmeister MA and Ayala JE: Exendin-4 attenuates high glucose-induced cardiomyocyte apoptosis via inhibition of endoplasmic reticulum stress and activation of SERCA2a. Am J Physiol Cell Physiol. 304:C508–C518. 2013. View Article : Google Scholar
46	Kuo WW, Wang WJ, Tsai CY, Way CL, Hsu HH and Chen LM: Diallyl trisufide (DATS) suppresses high glucose-induced cardiomyocyte apoptosis by inhibiting JNK/NFkappaB signaling via attenuating ROS generation. Int J Cardiol. View Article : Google Scholar : 2012.PubMed/NCBI
47	Yu XY, Geng YJ, Liang JL, et al: High levels of glucose induce apoptosis in cardiomyocyte via epigenetic regulation of the insulin-like growth factor receptor. Exp Cell Res. 316:2903–2909. 2010. View Article : Google Scholar : PubMed/NCBI