Histone deacetylase inhibition of cardiac autophagy in rats on a high‑fat diet with low‑dose streptozotocin-induced type 2 diabetes mellitus

Lee,Ting‑I; Bai,Kuan‑Jen; Chen,Yao‑Chang; Lee,Ting‑Wei; Chung,Cheng‑Chih; Tsai,Wen‑Chih; Tsao,Shin‑Yi; Kao,Yu‑Hsun

doi:10.3892/mmr.2017.7905

Histone deacetylase inhibition of cardiac autophagy in rats on a high‑fat diet with low‑dose streptozotocin-induced type 2 diabetes mellitus

Authors:
- Ting‑I Lee
- Kuan‑Jen Bai
- Yao‑Chang Chen
- Ting‑Wei Lee
- Cheng‑Chih Chung
- Wen‑Chih Tsai
- Shin‑Yi Tsao
- Yu‑Hsun Kao
View Affiliations

Affiliations: Department of General Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C., School of Respiratory Therapy, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C., Department of Biomedical Engineering, National Defense Medical Center, Taipei 11490, Taiwan, R.O.C., Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei 11696, Taiwan, R.O.C., Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan, R.O.C., Division of Cardiology, Tzu‑Chi General Hospital, Institute of Medical Sciences, Tzu‑Chi University, Hualien 97004, Taiwan, R.O.C., Division of Endocrinology and Metabolism, Department of Internal Medicine, Sijhih Cathay General Hospital, New Taipei City 22174, Taiwan, R.O.C.
Published online on: October 26, 2017 https://doi.org/10.3892/mmr.2017.7905
Pages: 594-601

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

Autophagy serves a role in preserving cellular homeostasis. Diabetes mellitus (DM) impairs cardiac autophagy and is associated with an accumulation of cytotoxic proteins that may provoke apoptosis and damage cardiomyocytes. Histone deacetylase (HDAC) inhibitors attenuate cardiac fibrosis and inflammation, and improve cardiomyopathy resulting from DM. However, the effect of HDAC inhibition on autophagy in DM cardiomyopathy has not been investigated. The purpose of the present study was to evaluate whether HDAC inhibition modulates cardiac autophagy and to investigate the potential mechanisms in type 2 DM (T2DM) hearts. Electrocardiography was used to evaluate cardiac function and western blotting was used to evaluate protein expression in autophagy, the serine/threonine protein kinase mTOR (mTOR) signaling pathway, poly adenosine diphosphate ribose polymerase 1 (PARP1), insulin signaling, advanced glycosylation end product‑specific receptor (RAGE), and proinflammatory cytokines in control rats and in rats treated with a high‑fat diet (60% fat) and low‑dose streptozotocin (35 mg/kg) in order to induce T2DM, with or without an HDAC inhibitor (MPT0E014; 50 mg/kg/rat daily for 7 days). Compared with the control rats, T2DM and T2DM rats treated with MPT0E014 exhibited elevated blood glucose levels and similar body weights. However, T2DM rats treated with MPT0E014 and control rats had a smaller left ventricular end‑diastolic diameter compared with the T2DM rats. The control and T2DM rats treated with MPT0E014 had greater protein expression of cardiac phosphorylated (p)‑5' adenosine monophosphate‑activated protein kinase α 2, light chain 3‑II, Beclin‑1, glucose transporter 4, p‑protein kinase B, and insulin receptor substrate‑1 (Ser 307) compared with T2DM rats. In addition, control and T2DM rats treated with MPT0E014 had decreased cardiac protein expression of cleaved PARP1, p‑mTOR‑S2448, p‑P70S6K‑Thr‑389, RAGE, tumor necrosis factor‑α, and interleukin‑6 compared with T2DM rats. The present study demonstrated that MPT0E014 may improve cardiac function in T2DM rats by modulating myocardial autophagy, inflammation and insulin signaling.

View Figures

View References

1	Simonson DC: Etiology and prevalence of hypertension in diabetic patients. Diabetes Care. 11:821–827. 1988. View Article : Google Scholar : PubMed/NCBI
2	Garcia MJ, McNamara PM, Gordon T and Kannel WB: Morbidity and mortality in diabetics in the Framingham population. Sixteen year follow-up study. Diabetes. 23:105–111. 1974. View Article : Google Scholar : PubMed/NCBI
3	Haffner SM, Lehto S, Rönnemaa T, Pyörälä K and Laakso M: Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 339:229–234. 1998. View Article : Google Scholar : PubMed/NCBI
4	Yang Z and Klionsky DJ: Eaten alive: A history of macroautophagy. Nat Cell Biol. 12:814–822. 2010. View Article : Google Scholar : PubMed/NCBI
5	Maiuri MC, Zalckvar E, Kimchi A and Kroemer G: Self-eating and self-killing: Crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 8:741–752. 2007. View Article : Google Scholar : PubMed/NCBI
6	Nishida K, Kyoi S, Yamaguchi O, Sadoshima J and Otsu K: The role of autophagy in the heart. Cell Death Differ. 16:31–38. 2009. View Article : Google Scholar : PubMed/NCBI
7	Gustafsson AB and Gottlieb RA: Autophagy in ischemic heart disease. Circ Res. 104:150–158. 2009. View Article : Google Scholar : PubMed/NCBI
8	Munasinghe PE, Riu F, Dixit P, Edamatsu M, Saxena P, Hamer NS, Galvin IF, Bunton RW, Lequeux S, Jones G, et al: Type-2 diabetes increases autophagy in the human heart through promotion of Beclin-1 mediated pathway. Int J Cardiol. 202:13–20. 2016. View Article : Google Scholar : PubMed/NCBI
9	Li ZL, Woollard JR, Ebrahimi B, Crane JA, Jordan KL, Lerman A, Wang SM and Lerman LO: Transition from obesity to metabolic syndrome is associated with altered myocardial autophagy and apoptosis. Arterioscler Thromb Vasc Biol. 32:1132–1141. 2012. View Article : Google Scholar : PubMed/NCBI
10	Mellor KM, Bell JR, Young MJ, Ritchie RH and Delbridge LM: Myocardial autophagy activation and suppressed survival signaling is associated with insulin resistance in fructose-fed mice. J Mol Cell Cardiol. 50:1035–1043. 2011. View Article : Google Scholar : PubMed/NCBI
11	Sciarretta S, Volpe M and Sadoshima J: Mammalian target of rapamycin signaling in cardiac physiology and disease. Circ Res. 114:549–564. 2014. View Article : Google Scholar : PubMed/NCBI
12	Kubli DA and Gustafsson AB: Cardiomyocyte health: Adapting to metabolic changes through autophagy. Trends Endocrinol Metab. 25:156–164. 2014. View Article : Google Scholar : PubMed/NCBI
13	Christensen DP, Dahllöf M, Lundh M, Rasmussen DN, Nielsen MD, Billestrup N, Grunnet LG and Mandrup-Poulsen T: Histone deacetylase (HDAC) inhibition as a novel treatment for diabetes mellitus. Mol Med. 17:378–390. 2011. View Article : Google Scholar : PubMed/NCBI
14	Sharma S and Taliyan R: Histone deacetylase inhibitors: Future therapeutics for insulin resistance and type 2 diabetes. Pharmacol Res. 113:320–326. 2016. View Article : Google Scholar : PubMed/NCBI
15	Kao YH, Liou JP, Chung CC, Lien GS, Kuo CC, Chen SA and Chen YJ: Histone deacetylase inhibition improved cardiac functions with direct antifibrotic activity in heart failure. Int J Cardiol. 168:4178–4183. 2013. View Article : Google Scholar : PubMed/NCBI
16	Lee TI, Kao YH, Tsai WC, Chung CC, Chen YC and Chen YJ: HDAC inhibition modulates cardiac PPARs and fatty acid metabolism in diabetic cardiomyopathy. PPAR Res. 2016:59387402016. View Article : Google Scholar : PubMed/NCBI
17	Brownlee M: Biochemistry and molecular cell biology of diabetic complications. Nature. 414:813–820. 2001. View Article : Google Scholar : PubMed/NCBI
18	Barlovic DP, Soro-Paavonen A and Jandeleit-Dahm KA: RAGE biology, atherosclerosis and diabetes. Clin Sci (Lond). 121:43–55. 2011. View Article : Google Scholar : PubMed/NCBI
19	Mansor LS, Gonzalez ER, Cole MA, Tyler DJ, Beeson JH, Clarke K, Carr CA and Heather LC: Cardiac metabolism in a new rat model of type 2 diabetes using high-fat diet with low dose streptozotocin. Cardiovasc Diabetol. 12:1362013. View Article : Google Scholar : PubMed/NCBI
20	Lee TI, Kao YH, Chen YC, Pan NH, Lin YK and Chen YJ: Cardiac peroxisome-proliferator-activated receptor expression in hypertension co-existing with diabetes. Clin Sci (Lond). 121:305–312. 2011. View Article : Google Scholar : PubMed/NCBI
21	Lee TI, Chen YC, Kao YH, Hsiao FC, Lin YK and Chen YJ: Rosiglitazone induces arrhythmogenesis in diabetic hypertensive rats with calcium handling alteration. Int J Cardiol. 165:299–307. 2013. View Article : Google Scholar : PubMed/NCBI
22	Lkhagva B, Lin YK, Kao YH, Chazo TF, Chung CC, Chen SA and Chen YJ: Novel histone deacetylase inhibitor modulates cardiac peroxisome proliferator-activated receptors and inflammatory cytokines in heart failure. Pharmacology. 96:184–191. 2015. View Article : Google Scholar : PubMed/NCBI
23	Cefalu WT: Animal models of type 2 diabetes: Clinical presentation and pathophysiological relevance to the human condition. ILAR J. 47:186–198. 2006. View Article : Google Scholar : PubMed/NCBI
24	Boden G, Lebed B, Schatz M, Homko C and Lemieux S: Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes. 50:1612–1617. 2001. View Article : Google Scholar : PubMed/NCBI
25	Haffner SM: American Diabetes Association: Management of dyslipidemia in adults with diabetes. Diabetes care. 26 Suppl 1:S83–S86. 2003. View Article : Google Scholar : PubMed/NCBI
26	Reaven GM, Hollenbeck C, Jeng CY, Wu MS and Chen YD: Measurement of plasma glucose, free fatty acid, lactate, and insulin for 24 h in patients with NIDDM. Diabetes. 37:1020–1024. 1988. View Article : Google Scholar : PubMed/NCBI
27	Shulman GI: Cellular mechanisms of insulin resistance. J Clin Invest. 106:171–176. 2000. View Article : Google Scholar : PubMed/NCBI
28	Srinivasan K, Viswanad B, Asrat L, Kaul CL and Ramarao P: Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: A model for type 2 diabetes and pharmacological screening. Pharmacol Res. 52:313–320. 2005. View Article : Google Scholar : PubMed/NCBI
29	Levine B and Kroemer G: Autophagy in the pathogenesis of disease. Cell. 132:27–42. 2008. View Article : Google Scholar : PubMed/NCBI
30	Singh R and Cuervo AM: Autophagy in the cellular energetic balance. Cell Metab. 13:495–504. 2011. View Article : Google Scholar : PubMed/NCBI
31	Sciarretta S, Zhai P, Shao D, Maejima Y, Robbins J, Volpe M, Condorelli G and Sadoshima J: Rheb is a critical regulator of autophagy during myocardial ischemia: Pathophysiological implications in obesity and metabolic syndrome. Circulation. 125:1134–1146. 2012. View Article : Google Scholar : PubMed/NCBI
32	He C, Zhu H, Li H, Zou MH and Xie Z: Dissociation of Bcl-2-Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes. Diabetes. 62:1270–1281. 2013. View Article : Google Scholar : PubMed/NCBI
33	Guo R, Zhang Y, Turdi S and Ren J: Adiponectin knockout accentuates high fat diet-induced obesity and cardiac dysfunction: Role of autophagy. Biochim Biophys Acta. 1832:1136–1148. 2013. View Article : Google Scholar : PubMed/NCBI
34	Xu X and Ren J: Macrophage migration inhibitory factor (MIF) knockout preserves cardiac homeostasis through alleviating Akt-mediated myocardial autophagy suppression in high-fat diet-induced obesity. Int J Obes (Lond). 39:387–396. 2015. View Article : Google Scholar : PubMed/NCBI
35	Inoki K, Zhu T and Guan KL: TSC2 mediates cellular energy response to control cell growth and survival. Cell. 115:577–590. 2003. View Article : Google Scholar : PubMed/NCBI
36	Lum JJ, DeBerardinis RJ and Thompson CB: Autophagy in metazoans: Cell survival in the land of plenty. Nat Rev Mol Cell Biol. 6:439–448. 2005. View Article : Google Scholar : PubMed/NCBI
37	Sun L, Ishida T, Yasuda T, Kojima Y, Honjo T, Yamamoto Y, Yamamoto H, Ishibashi S, Hirata K and Hayashi Y: RAGE mediates oxidized LDL-induced pro-inflammatory effects and atherosclerosis in non-diabetic LDL receptor-deficient mice. Cardiovasc Res. 82:371–381. 2009. View Article : Google Scholar : PubMed/NCBI
38	Zisman A, Peroni OD, Abel ED, Michael MD, Mauvais-Jarvis F, Lowell BB, Wojtaszewski JF, Hirshman MF, Virkamaki A, Goodyear LJ, et al: Targeted disruption of the glucose transporter 4 selectively in muscle causes insulin resistance and glucose intolerance. Nat Med. 6:924–928. 2000. View Article : Google Scholar : PubMed/NCBI
39	Lin HV, Ren H, Samuel VT, Lee HY, Lu TY, Shulman GI and Accili D: Diabetes in mice with selective impairment of insulin action in Glut4-expressing tissues. Diabetes. 60:700–709. 2011. View Article : Google Scholar : PubMed/NCBI
40	Chao KC, Chao KF, Fu YS and Liu SH: Islet-like clusters derived from mesenchymal stem cells in Wharton's Jelly of the human umbilical cord for transplantation to control type 1 diabetes. PLoS One. 3:e14512008. View Article : Google Scholar : PubMed/NCBI