J Lipid Atheroscler.  2019 May;8(1):26-47. 10.12997/jla.2019.8.1.26.

Established and Emerging Mechanisms of Diabetic Cardiomyopathy

• Gollmer J
• Zirlik A
• Bugger H

• KMID: 2447754
• DOI: http://doi.org/10.12997/jla.2019.8.1.26

Abstract

Diabetes mellitus increases the risk for the development of heart failure even in the absence of coronary artery disease and hypertension, a cardiac entity termed diabetic cardiomyopathy (DC). Clinically, DC is increasingly recognized and typically characterized by concentric cardiac hypertrophy and diastolic dysfunction, ultimately resulting in heart failure with preserved ejection fraction (HFpEF) and potentially even heart failure with reduced ejection fraction (HFrEF). Numerous molecular mechanisms have been proposed to underlie the alterations in myocardial structure and function in DC, many of which show similar alterations in the failing heart. Well investigated and established mechanisms of DC include increased myocardial fibrosis, enhanced apoptosis, oxidative stress, impaired intracellular calcium handling, substrate metabolic alterations, and inflammation, among others. In addition, a number of novel mechanisms that receive increasing attention have been identified in recent years, including autophagy, dysregulation of microRNAs, epigenetic mechanisms, and alterations in mitochondrial protein acetylation, dynamics and quality control. This review aims to provide an overview and update of established underlying mechanisms of DC, as well as a discussion of recently identified and emerging mechanisms that may also contribute to the structural and functional alterations in DC.

Keyword

Diabetes mellitus; Heart failure; Diabetic cardiomyopathy

MeSH Terms

Acetylation
Apoptosis
Autophagy
Calcium
Cardiomegaly
Coronary Artery Disease
Diabetes Mellitus
Diabetic Cardiomyopathies*
Epigenomics
Fibrosis
Heart
Heart Failure
Hypertension
Inflammation
MicroRNAs
Mitochondrial Proteins
Oxidative Stress
Quality Control
Calcium
MicroRNAs
Mitochondrial Proteins

Figure

• 

  Fig. 1 Consequences of diabetes-induced alterations in substrate metabolism and sources of increased ROS in DC. Increased FA uptake results in accumulation of TAG, lipid intermediates and increased FA oxidation, all of which may harm the cardiomyocyte. Increased glucose entry into the cardiomyocyte may promote alternative pathways of glucose utilization, thus provoking an increase in ROS, AGE, and O-GlcNAcylation. Increased amounts of intramitochondrial ROS may be generated by the electron transport chain, by increased MAO activity or by increased calpain-1 levels, whereas NOX2, NOX4, and XO may contribute to increased cytosolic ROS generation. ROS, reactive oxygen species; DC, diabetic cardiomyopathy; FA, fatty acid; TAG, triacylglycerols; AGE, advanced glycation end product; NOX, NADPH oxidases; XO, xanthine oxidase; GLUT, glucose transport protein; CD, cluster of differentiation; FATP, fatty acid transport protein; ACS, acetyl-CoA synthetase; PPARα, peroxisome proliferator-activated receptor α; FAO, fatty acid oxidation; PPP, pentose phosphate pathway; NADPH, nicotinamide adenine dinucleotide phosphate; HBP, hexosamine biosynthetic pathway; O-GlcNAc, O-linked β-N-acetylglucosamine; SERCA, sarco(endo) plasmic reticulum Ca2+-ATPase; DAG, diacylglycerols; TAG, triacylglycerols; CPT, carnitine palmitoyltransferase; TCA, trichloroacetic acid; MAO, monoamine oxidases; PDH, pyruvate dehydrogenase; ADP, adenosine diphosphate; ATP, adenosine triphosphate; UCP, uncoupling protein.

• 

  Fig. 2 Potential mechanisms and effects of impaired Ca2+ handling in DC. Impairment in cardiomyocyte Ca2+ influx and efflux, impaired release and reuptake of Ca2+ by the SR, and impaired Ca2+ uptake by the mitochondria which may subsequently impair ATP regeneration and thereby contribute to systolic and diastolic dysfunction in DC. DC, diabetic cardiomyopathy; SR, sarcoplasmic reticulum; ATP, adenosine triphosphate; NCX, Na+/Ca2+ exchanger; LTCC, L-type Ca2+ channels; TCA, trichloroacetic acid; DH, dehydrogenase; RyR, ryanodine receptor; CaMKII, calmodulin-dependent protein kinase II; O-GlcNAc, O-linked β-N-acetylglucosamine; SERCA, sarco(endo)plasmic reticulum Ca2+-ATPase; AGE, advanced glycation end product.

• 

  Fig. 3 Novel mitochondrial mechanisms potentially contributing to DC. Decreased SIRT3 activity in DC may contribute to impaired oxidative ATP regeneration, increased ROS production and suppression of mitophagy. MAO and calpain 1 may contribute to increased mitochondrial ROS. O-GlcNAcylation and acyl-CoA driven posttranslational modification of Drp1 and Opa1 may contribute to mitochondrial fragmentation. Decreased levels of PINK and Parkin may suppress mitophagy in DC. Mitochondrial fragmentation and suppression of mitophagy may further amplify mitochondrial dysfunction in DC. DC, diabetic cardiomyopathy; SIRT3, sirtuin 3; ATP, adenosine triphosphate; ROS, reactive oxygen species; MAO, monoamine oxidases; O-GlcNAc, O-linked β-N-acetylglucosamine; TCA, trichloroacetic acid.

Reference

1. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol. 1972; 30:595–602.

2. Devereux RB, Roman MJ, Paranicas M, O'Grady MJ, Lee ET, Welty TK, et al. Impact of diabetes on cardiac structure and function: the strong heart study. Circulation. 2000; 101:2271–2276.

3. Seferović PM, Paulus WJ. Clinical diabetic cardiomyopathy: a two-faced disease with restrictive and dilated phenotypes. Eur Heart J. 2015; 36:1718–1727.

4. Boyer JK, Thanigaraj S, Schechtman KB, Pérez JE. Prevalence of ventricular diastolic dysfunction in asymptomatic, normotensive patients with diabetes mellitus. Am J Cardiol. 2004; 93:870–875.

5. Fang ZY, Schull-Meade R, Leano R, Mottram PM, Prins JB, Marwick TH. Screening for heart disease in diabetic subjects. Am Heart J. 2005; 149:349–354.

6. Fillmore N, Mori J, Lopaschuk GD. Mitochondrial fatty acid oxidation alterations in heart failure, ischaemic heart disease and diabetic cardiomyopathy. Br J Pharmacol. 2014; 171:2080–2090.

7. Finck BN, Lehman JJ, Leone TC, Welch MJ, Bennett MJ, Kovacs A, et al. The cardiac phenotype induced by PPARα overexpression mimics that caused by diabetes mellitus. J Clin Invest. 2002; 109:121–130.

8. Boudina S, Sena S, Theobald H, Sheng X, Wright JJ, Hu XX, et al. Mitochondrial energetics in the heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes. 2007; 56:2457–2466.

9. Bugger H, Abel ED. Molecular mechanisms for myocardial mitochondrial dysfunction in the metabolic syndrome. Clin Sci (Lond). 2008; 114:195–210.

10. Larsen TS, Aasum E. Metabolic (in)flexibility of the diabetic heart. Cardiovasc Drugs Ther. 2008; 22:91–95.

11. Aasum E, Hafstad AD, Severson DL, Larsen TS. Age-dependent changes in metabolism, contractile function, and ischemic sensitivity in hearts from db/db mice. Diabetes. 2003; 52:434–441.

12. van Bilsen M, Daniels A, Brouwers O, Janssen BJ, Derks WJ, Brouns AE, et al. Hypertension is a conditional factor for the development of cardiac hypertrophy in type 2 diabetic mice. PLoS One. 2014; 9:e85078.

13. Zlobine I, Gopal K, Ussher JR. Lipotoxicity in obesity and diabetes-related cardiac dysfunction. Biochim Biophys Acta. 2016; 1861:1555–1568.

14. Nakamura M, Liu T, Husain S, Zhai P, Warren JS, Hsu CP, et al. Glycogen synthase kinase-3α promotes fatty acid uptake and lipotoxic cardiomyopathy. Cell Metab. 2019.

15. Kienesberger PC, Pulinilkunnil T, Nagendran J, Young ME, Bogner-Strauss JG, Hackl H, et al. Early structural and metabolic cardiac remodelling in response to inducible adipose triglyceride lipase ablation. Cardiovasc Res. 2013; 99:442–451.

16. Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, et al. Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci U S A. 2000; 97:1784–1789.

17. Park TS, Hu Y, Noh HL, Drosatos K, Okajima K, Buchanan J, et al. Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. J Lipid Res. 2008; 49:2101–2112.

18. Russo SB, Baicu CF, Van Laer A, Geng T, Kasiganesan H, Zile MR, et al. Ceramide synthase 5 mediates lipid-induced autophagy and hypertrophy in cardiomyocytes. J Clin Invest. 2012; 122:3919–3930.

19. Kuo TH, Giacomelli F, Wiener J, Lapanowski-Netzel K. Pyruvate dehydrogenase activity in cardiac mitochondria from genetically diabetic mice. Diabetes. 1985; 34:1075–1081.

20. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001; 414:813–820.

21. Serpillon S, Floyd BC, Gupte RS, George S, Kozicky M, Neito V, et al. Superoxide production by NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate dehydrogenase-derived NADPH. Am J Physiol Heart Circ Physiol. 2009; 297:H153–H162.

22. Li SY, Sigmon VK, Babcock SA, Ren J. Advanced glycation endproduct induces ROS accumulation, apoptosis, MAP kinase activation and nuclear O-GlcNAcylation in human cardiac myocytes. Life Sci. 2007; 80:1051–1056.

23. Bidasee KR, Zhang Y, Shao CH, Wang M, Patel KP, Dincer UD, et al. Diabetes increases formation of advanced glycation end products on Sarco(endo)plasmic reticulum Ca²⁺-ATPase. Diabetes. 2004; 53:463–473.

24. Shao CH, Rozanski GJ, Patel KP, Bidasee KR. Dyssynchronous (non-uniform) Ca²⁺ release in myocytes from streptozotocin-induced diabetic rats. J Mol Cell Cardiol. 2007; 42:234–246.

25. Kranstuber AL, Del Rio C, Biesiadecki BJ, Hamlin RL, Ottobre J, Gyorke S, et al. Advanced glycation end product cross-link breaker attenuates diabetes-induced cardiac dysfunction by improving sarcoplasmic reticulum calcium handling. Front Physiol. 2012; 3:292.

26. Goldin A, Beckman JA, Schmidt AM, Creager MA. Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation. 2006; 114:597–605.

27. Clark RJ, McDonough PM, Swanson E, Trost SU, Suzuki M, Fukuda M, et al. Diabetes and the accompanying hyperglycemia impairs cardiomyocyte calcium cycling through increased nuclear O-GlcNAcylation. J Biol Chem. 2003; 278:44230–44237.

28. Anderson EJ, Kypson AP, Rodriguez E, Anderson CA, Lehr EJ, Neufer PD. Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart. J Am Coll Cardiol. 2009; 54:1891–1898.

29. Lashin OM, Szweda PA, Szweda LI, Romani AM. Decreased complex II respiration and HNE-modified SDH subunit in diabetic heart. Free Radic Biol Med. 2006; 40:886–896.

30. Ye G, Metreveli NS, Donthi RV, Xia S, Xu M, Carlson EC, et al. Catalase protects cardiomyocyte function in models of type 1 and type 2 diabetes. Diabetes. 2004; 53:1336–1343.

31. Cong W, Ruan D, Xuan Y, Niu C, Tao Y, Wang Y, et al. Cardiac-specific overexpression of catalase prevents diabetes-induced pathological changes by inhibiting NF-κB signaling activation in the heart. J Mol Cell Cardiol. 2015; 89:314–325.

32. Arkat S, Umbarkar P, Singh S, Sitasawad SL. Mitochondrial Peroxiredoxin-3 protects against hyperglycemia induced myocardial damage in Diabetic cardiomyopathy. Free Radic Biol Med. 2016; 97:489–500.

33. Shen X, Zheng S, Metreveli NS, Epstein PN. Protection of cardiac mitochondria by overexpression of MnSOD reduces diabetic cardiomyopathy. Diabetes. 2006; 55:798–805.

34. Ni R, Cao T, Xiong S, Ma J, Fan GC, Lacefield JC, et al. Therapeutic inhibition of mitochondrial reactive oxygen species with mito-TEMPO reduces diabetic cardiomyopathy. Free Radic Biol Med. 2016; 90:12–23.

35. Teshima Y, Takahashi N, Nishio S, Saito S, Kondo H, Fukui A, et al. Production of reactive oxygen species in the diabetic heart. Roles of mitochondria and NADPH oxidase. Circ J. 2014; 78:300–306.

36. Shen E, Li Y, Li Y, Shan L, Zhu H, Feng Q, et al. Rac1 is required for cardiomyocyte apoptosis during hyperglycemia. Diabetes. 2009; 58:2386–2395.

37. Roe ND, Thomas DP, Ren J. Inhibition of NADPH oxidase alleviates experimental diabetes-induced myocardial contractile dysfunction. Diabetes Obes Metab. 2011; 13:465–473.

38. Rajesh M, Mukhopadhyay P, Bátkai S, Mukhopadhyay B, Patel V, Haskó G, et al. Xanthine oxidase inhibitor allopurinol attenuates the development of diabetic cardiomyopathy. J Cell Mol Med. 2009; 13:2330–2341.

39. Gao X, Xu Y, Xu B, Liu Y, Cai J, Liu HM, et al. Allopurinol attenuates left ventricular dysfunction in rats with early stages of streptozotocin-induced diabetes. Diabetes Metab Res Rev. 2012; 28:409–417.

40. Zou MH, Shi C, Cohen RA. Oxidation of the zinc-thiolate complex and uncoupling of endothelial nitric oxide synthase by peroxynitrite. J Clin Invest. 2002; 109:817–826.

41. Jo H, Otani H, Jo F, Shimazu T, Okazaki T, Yoshioka K, et al. Inhibition of nitric oxide synthase uncoupling by sepiapterin improves left ventricular function in streptozotocin-induced diabetic mice. Clin Exp Pharmacol Physiol. 2011; 38:485–493.

42. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. 2007; 87:315–424.

43. Shimizu M, Umeda K, Sugihara N, Yoshio H, Ino H, Takeda R, et al. Collagen remodelling in myocardia of patients with diabetes. J Clin Pathol. 1993; 46:32–36.

44. Mizushige K, Yao L, Noma T, Kiyomoto H, Yu Y, Hosomi N, et al. Alteration in left ventricular diastolic filling and accumulation of myocardial collagen at insulin-resistant prediabetic stage of a type II diabetic rat model. Circulation. 2000; 101:899–907.

45. Baicu CF, Stroud JD, Livesay VA, Hapke E, Holder J, Spinale FG, et al. Changes in extracellular collagen matrix alter myocardial systolic performance. Am J Physiol Heart Circ Physiol. 2003; 284:H122–H132.

46. Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci. 2014; 71:549–574.

47. Chiu J, Farhangkhoee H, Xu BY, Chen S, George B, Chakrabarti S. PARP mediates structural alterations in diabetic cardiomyopathy. J Mol Cell Cardiol. 2008; 45:385–393.

48. Asbun J, Villarreal FJ. The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy. J Am Coll Cardiol. 2006; 47:693–700.

49. Ban CR, Twigg SM. Fibrosis in diabetes complications: pathogenic mechanisms and circulating and urinary markers. Vasc Health Risk Manag. 2008; 4:575–596.

50. Westermann D, Rutschow S, Jäger S, Linderer A, Anker S, Riad A, et al. Contributions of inflammation and cardiac matrix metalloproteinase activity to cardiac failure in diabetic cardiomyopathy: the role of angiotensin type 1 receptor antagonism. Diabetes. 2007; 56:641–646.

51. Ronnebaum SM, Patterson C. The FoxO family in cardiac function and dysfunction. Annu Rev Physiol. 2010; 72:81–94.

52. Battiprolu PK, Hojayev B, Jiang N, Wang ZV, Luo X, Iglewski M, et al. Metabolic stress-induced activation of FoxO1 triggers diabetic cardiomyopathy in mice. J Clin Invest. 2012; 122:1109–1118.

53. Frustaci A, Kajstura J, Chimenti C, Jakoniuk I, Leri A, Maseri A, et al. Myocardial cell death in human diabetes. Circ Res. 2000; 87:1123–1132.

54. Fuentes-Antrás J, Ioan AM, Tuñón J, Egido J, Lorenzo O. Activation of toll-like receptors and inflammasome complexes in the diabetic cardiomyopathy-associated inflammation. Int J Endocrinol. 2014; 2014:847827.

55. Westermann D, Van Linthout S, Dhayat S, Dhayat N, Escher F, Bücker-Gärtner C, et al. Cardioprotective and anti-inflammatory effects of interleukin converting enzyme inhibition in experimental diabetic cardiomyopathy. Diabetes. 2007; 56:1834–1841.

56. Tschöpe C, Walther T, Escher F, Spillmann F, Du J, Altmann C, et al. Transgenic activation of the kallikrein-kinin system inhibits intramyocardial inflammation, endothelial dysfunction and oxidative stress in experimental diabetic cardiomyopathy. FASEB J. 2005; 19:2057–2059.

57. Varga ZV, Giricz Z, Liaudet L, Haskó G, Ferdinandy P, Pacher P. Interplay of oxidative, nitrosative/nitrative stress, inflammation, cell death and autophagy in diabetic cardiomyopathy. Biochim Biophys Acta. 2015; 1852:232–242.

58. Li YY, Feng YQ, Kadokami T, McTiernan CF, Draviam R, Watkins SC, et al. Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by anti-tumor necrosis factor alpha therapy. Proc Natl Acad Sci U S A. 2000; 97:12746–12751.

59. Zhang Y, Peng T, Zhu H, Zheng X, Zhang X, Jiang N, et al. Prevention of hyperglycemia-induced myocardial apoptosis by gene silencing of Toll-like receptor-4. J Transl Med. 2010; 8:133.

60. Ko HJ, Zhang Z, Jung DY, Jun JY, Ma Z, Jones KE, et al. Nutrient stress activates inflammation and reduces glucose metabolism by suppressing AMP-activated protein kinase in the heart. Diabetes. 2009; 58:2536–2546.

61. Dong B, Yu QT, Dai HY, Gao YY, Zhou ZL, Zhang L, et al. Angiotensin-converting enzyme-2 overexpression improves left ventricular remodeling and function in a rat model of diabetic cardiomyopathy. J Am Coll Cardiol. 2012; 59:739–747.

62. Guarda G, So A. Regulation of inflammasome activity. Immunology. 2010; 130:329–336.

63. Luo B, Li B, Wang W, Liu X, Xia Y, Zhang C, et al. NLRP3 gene silencing ameliorates diabetic cardiomyopathy in a type 2 diabetes rat model. PLoS One. 2014; 9:e104771.

64. Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ. Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes. 2002; 51:1938–1948.

65. Chowdhry MF, Vohra HA, Galiñanes M. Diabetes increases apoptosis and necrosis in both ischemic and nonischemic human myocardium: role of caspases and poly-adenosine diphosphate-ribose polymerase. J Thorac Cardiovasc Surg. 2007; 134:124–131.

66. Ouyang C, You J, Xie Z. The interplay between autophagy and apoptosis in the diabetic heart. J Mol Cell Cardiol. 2014; 71:71–80.

67. Bojunga J, Nowak D, Mitrou PS, Hoelzer D, Zeuzem S, Chow KU. Antioxidative treatment prevents activation of death-receptor- and mitochondrion-dependent apoptosis in the hearts of diabetic rats. Diabetologia. 2004; 47:2072–2080.

68. He C, Zhu H, Li H, Zou MH, Xie Z. Dissociation of Bcl-2-Beclin1 complex by activated AMPK enhances cardiac autophagy and protects against cardiomyocyte apoptosis in diabetes. Diabetes. 2013; 62:1270–1281.

69. Yang L, Zhao D, Ren J, Yang J. Endoplasmic reticulum stress and protein quality control in diabetic cardiomyopathy. Biochim Biophys Acta. 2015; 1852:209–218.

70. Bergh CH, Hjalmarson A, Sjögren KG, Jacobsson B. The effect of diabetes on phosphatidylinositol turnover and calcium influx in myocardium. Horm Metab Res. 1988; 20:381–386.

71. Lacombe VA, Viatchenko-Karpinski S, Terentyev D, Sridhar A, Emani S, Bonagura JD, et al. Mechanisms of impaired calcium handling underlying subclinical diastolic dysfunction in diabetes. Am J Physiol Regul Integr Comp Physiol. 2007; 293:R1787–R1797.

72. Isenberg G, Han S, Schiefer A, Wendt-Gallitelli MF. Changes in mitochondrial calcium concentration during the cardiac contraction cycle. Cardiovasc Res. 1993; 27:1800–1809.

73. Territo PR, Mootha VK, French SA, Balaban RS. Ca²⁺ activation of heart mitochondrial oxidative phosphorylation: role of the F₀/F₁-ATPase. Am J Physiol Cell Physiol. 2000; 278:C423–C435.

74. Pereira L, Matthes J, Schuster I, Valdivia HH, Herzig S, Richard S, et al. Mechanisms of [Ca²⁺]_i transient decrease in cardiomyopathy of db/db type 2 diabetic mice. Diabetes. 2006; 55:608–615.

75. Pereira L, Ruiz-Hurtado G, Rueda A, Mercadier JJ, Benitah JP, Gómez AM. Calcium signaling in diabetic cardiomyocytes. Cell Calcium. 2014; 56:372–380.

76. Erickson JR, Pereira L, Wang L, Han G, Ferguson A, Dao K, et al. Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation. Nature. 2013; 502:372–376.

77. Mandavia CH, Aroor AR, Demarco VG, Sowers JR. Molecular and metabolic mechanisms of cardiac dysfunction in diabetes. Life Sci. 2013; 92:601–608.

78. Palomeque J, Delbridge L, Petroff MV. Angiotensin II: a regulator of cardiomyocyte function and survival. Front Biosci (Landmark Ed). 2009; 14:5118–5133.

79. Nagatomo Y, Meguro T, Ito H, Koide K, Anzai T, Fukuda K, et al. Significance of AT1 receptor independent activation of mineralocorticoid receptor in murine diabetic cardiomyopathy. PLoS One. 2014; 9:e93145.

80. Van Linthout S, Seeland U, Riad A, Eckhardt O, Hohl M, Dhayat N, et al. Reduced MMP-2 activity contributes to cardiac fibrosis in experimental diabetic cardiomyopathy. Basic Res Cardiol. 2008; 103:319–327.

81. Mori J, Patel VB, Abo Alrob O, Basu R, Altamimi T, Desaulniers J, et al. Angiotensin 1-7 ameliorates diabetic cardiomyopathy and diastolic dysfunction in db/db mice by reducing lipotoxicity and inflammation. Circ Heart Fail. 2014; 7:327–339.

82. Orea-Tejeda A, Colín-Ramírez E, Castillo-Martínez L, Asensio-Lafuente E, Corzo-León D, González-Toledo R, et al. Aldosterone receptor antagonists induce favorable cardiac remodeling in diastolic heart failure patients. Rev Invest Clin. 2007; 59:103–107.

83. Dong B, Yu QT, Dai HY, Gao YY, Zhou ZL, Zhang L, et al. Angiotensin-converting enzyme-2 overexpression improves left ventricular remodeling and function in a rat model of diabetic cardiomyopathy. J Am Coll Cardiol. 2012; 59:739–747.

84. Nakai A, Yamaguchi O, Takeda T, Higuchi Y, Hikoso S, Taniike M, et al. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med. 2007; 13:619–624.

85. Riehle C, Wende AR, Sena S, Pires KM, Pereira RO, Zhu Y, et al. Insulin receptor substrate signaling suppresses neonatal autophagy in the heart. J Clin Invest. 2013; 123:5319–5333.

86. Xie Z, Lau K, Eby B, Lozano P, He C, Pennington B, et al. Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice. Diabetes. 2011; 60:1770–1778.

87. Zhao Y, Zhang L, Qiao Y, Zhou X, Wu G, Wang L, et al. Heme oxygenase-1 prevents cardiac dysfunction in streptozotocin-diabetic mice by reducing inflammation, oxidative stress, apoptosis and enhancing autophagy. PLoS One. 2013; 8:e75927.

88. Xu X, Kobayashi S, Chen K, Timm D, Volden P, Huang Y, et al. Diminished autophagy limits cardiac injury in mouse models of type 1 diabetes. J Biol Chem. 2013; 288:18077–18092.

89. Kobayashi S, Liang Q. Autophagy and mitophagy in diabetic cardiomyopathy. Biochim Biophys Acta. 2015; 1852:252–261.

90. Xu X, Hua Y, Nair S, Zhang Y, Ren J. Akt2 knockout preserves cardiac function in high-fat diet-induced obesity by rescuing cardiac autophagosome maturation. J Mol Cell Biol. 2013; 5:61–63.

91. Guo R, Zhang Y, Turdi S, Ren J. Adiponectin knockout accentuates high fat diet-induced obesity and cardiac dysfunction: role of autophagy. Biochim Biophys Acta. 2013; 1832:1136–1148.

92. Kobayashi S, Xu X, Chen K, Liang Q. Suppression of autophagy is protective in high glucose-induced cardiomyocyte injury. Autophagy. 2012; 8:577–592.

93. Cetrullo S, Tantini B, Flamigni F, Pazzini C, Facchini A, Stefanelli C, et al. Antiapoptotic and antiautophagic effects of eicosapentaenoic acid in cardiac myoblasts exposed to palmitic acid. Nutrients. 2012; 4:78–90.

94. Galloway CA, Yoon Y. Mitochondrial dynamics in diabetic cardiomyopathy. Antioxid Redox Signal. 2015; 22:1545–1562.

95. Dabkowski ER, Williamson CL, Bukowski VC, Chapman RS, Leonard SS, Peer CJ, et al. Diabetic cardiomyopathy-associated dysfunction in spatially distinct mitochondrial subpopulations. Am J Physiol Heart Circ Physiol. 2009; 296:H359–H369.

96. Montaigne D, Marechal X, Coisne A, Debry N, Modine T, Fayad G, et al. Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients. Circulation. 2014; 130:554–564.

97. Gawlowski T, Suarez J, Scott B, Torres-Gonzalez M, Wang H, Schwappacher R, et al. Modulation of dynamin-related protein 1 (DRP1) function by increased O-linked-β-N-acetylglucosamine modification (O-GlcNAc) in cardiac myocytes. J Biol Chem. 2012; 287:30024–30034.

98. Makino A, Suarez J, Gawlowski T, Han W, Wang H, Scott BT, et al. Regulation of mitochondrial morphology and function by O-GlcNAcylation in neonatal cardiac myocytes. Am J Physiol Regul Integr Comp Physiol. 2011; 300:R1296–R1302.

99. Makino A, Scott BT, Dillmann WH. Mitochondrial fragmentation and superoxide anion production in coronary endothelial cells from a mouse model of type 1 diabetes. Diabetologia. 2010; 53:1783–1794.

100. Tsushima K, Bugger H, Wende AR, Soto J, Jenson GA, Tor AR, et al. Mitochondrial reactive oxygen species in lipotoxic hearts induce post-translational modifications of AKAP121, DRP1, and OPA1 that promote mitochondrial fission. Circ Res. 2018; 122:58–73.

101. Tang Y, Liu J, Long J. Phosphatase and tensin homolog-induced putative kinase 1 and Parkin in diabetic heart: role of mitophagy. J Diabetes Investig. 2015; 6:250–255.

102. Tong M, Saito T, Zhai P, Oka SI, Mizushima W, Nakamura M, et al. Mitophagy is essential for maintaining cardiac function during high fat diet-induced diabetic cardiomyopathy. Circ Res. 2019; 124:1360–1371.

103. Song M, Gong G, Burelle Y, Gustafsson AB, Kitsis RN, Matkovich SJ, et al. Interdependence of Parkin-mediated mitophagy and mitochondrial fission in adult mouse hearts. Circ Res. 2015; 117:346–351.

104. Bugger H, Abel ED. Mitochondria in the diabetic heart. Cardiovasc Res. 2010; 88:229–240.

105. Vazquez EJ, Berthiaume JM, Kamath V, Achike O, Buchanan E, Montano MM, et al. Mitochondrial complex I defect and increased fatty acid oxidation enhance protein lysine acetylation in the diabetic heart. Cardiovasc Res. 2015; 107:453–465.

106. Sultana MR, Bagul PK, Katare PB, Anwar Mohammed S, Padiya R, Banerjee SK. Garlic activates SIRT-3 to prevent cardiac oxidative stress and mitochondrial dysfunction in diabetes. Life Sci. 2016; 164:42–51.

107. Yu W, Gao B, Li N, Wang J, Qiu C, Zhang G, et al. Sirt3 deficiency exacerbates diabetic cardiac dysfunction: role of Foxo3A-Parkin-mediated mitophagy. Biochim Biophys Acta Mol Basis Dis. 2017; 1863:1973–1983.

108. Karamanlidis G, Lee CF, Garcia-Menendez L, Kolwicz SC Jr, Suthammarak W, Gong G, et al. Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell Metab. 2013; 18:239–250.

109. Koentges C, Pfeil K, Schnick T, Wiese S, Dahlbock R, Cimolai MC, et al. SIRT3 deficiency impairs mitochondrial and contractile function in the heart. Basic Res Cardiol. 2015; 110:36.

110. Ni R, Zheng D, Xiong S, Hill DJ, Sun T, Gardiner RB, et al. Mitochondrial calpain-1 disrupts ATP synthase and induces superoxide generation in type 1 diabetic hearts: a novel mechanism contributing to diabetic cardiomyopathy. Diabetes. 2016; 65:255–268.

111. Sturza A, Duicu OM, Vaduva A, Dănilă MD, Noveanu L, Varró A, et al. Monoamine oxidases are novel sources of cardiovascular oxidative stress in experimental diabetes. Can J Physiol Pharmacol. 2015; 93:555–561.

112. Wu S, Lu Q, Ding Y, Wu Y, Qiu Y, Wang P, et al. Hyperglycemia-driven inhibition of AMP-activated protein kinase α2 induces diabetic cardiomyopathy by promoting mitochondria-associated endoplasmic reticulum membranes in vivo . Circulation. 2019; 139:1913–1936.

113. Kaludercic N, Mialet-Perez J, Paolocci N, Parini A, Di Lisa F. Monoamine oxidases as sources of oxidants in the heart. J Mol Cell Cardiol. 2014; 73:34–42.

114. Wende AR. Post-translational modifications of the cardiac proteome in diabetes and heart failure. Proteomics Clin Appl. 2016; 10:25–38.

115. Hu Y, Belke D, Suarez J, Swanson E, Clark R, Hoshijima M, et al. Adenovirus-mediated overexpression of O-GlcNAcase improves contractile function in the diabetic heart. Circ Res. 2005; 96:1006–1013.

116. Banerjee PS, Ma J, Hart GW. Diabetes-associated dysregulation of O-GlcNAcylation in rat cardiac mitochondria. Proc Natl Acad Sci U S A. 2015; 112:6050–6055.

117. Aguilar H, Fricovsky E, Ihm S, Schimke M, Maya-Ramos L, Aroonsakool N, et al. Role for high-glucose-induced protein O-GlcNAcylation in stimulating cardiac fibroblast collagen synthesis. Am J Physiol Cell Physiol. 2014; 306:C794–C804.

118. Chen JF, Murchison EP, Tang R, Callis TE, Tatsuguchi M, Deng Z, et al. Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure. Proc Natl Acad Sci U S A. 2008; 105:2111–2116.

119. Costantino S, Paneni F, Lüscher TF, Cosentino F. MicroRNA profiling unveils hyperglycaemic memory in the diabetic heart. Eur Heart J. 2016; 37:572–576.

120. Katare R, Caporali A, Zentilin L, Avolio E, Sala-Newby G, Oikawa A, et al. Intravenous gene therapy with PIM-1 via a cardiotropic viral vector halts the progression of diabetic cardiomyopathy through promotion of prosurvival signaling. Circ Res. 2011; 108:1238–1251.

121. Xiao J, Luo X, Lin H, Zhang Y, Lu Y, Wang N, et al. MicroRNA miR-133 represses HERG K⁺ channel expression contributing to QT prolongation in diabetic hearts. J Biol Chem. 2007; 282:12363–12367.

122. Duisters RF, Tijsen AJ, Schroen B, Leenders JJ, Lentink V, van der Made I, et al. miR-133 and miR-30 regulate connective tissue growth factor: implications for a role of microRNAs in myocardial matrix remodeling. Circ Res. 2009; 104:170–178.

123. Zheng D, Ma J, Yu Y, Li M, Ni R, Wang G, et al. Silencing of miR-195 reduces diabetic cardiomyopathy in C57BL/6 mice. Diabetologia. 2015; 58:1949–1958.

124. Kuwabara Y, Horie T, Baba O, Watanabe S, Nishiga M, Usami S, et al. MicroRNA-451 exacerbates lipotoxicity in cardiac myocytes and high-fat diet-induced cardiac hypertrophy in mice through suppression of the LKB1/AMPK pathway. Circ Res. 2015; 116:279–288.

125. Raut SK, Kumar A, Singh GB, Nahar U, Sharma V, Mittal A, et al. miR-30c mediates upregulation of Cdc42 and Pak1 in diabetic cardiomyopathy. Cardiovasc Ther. 2015; 33:89–97.

126. Li X, Du N, Zhang Q, Li J, Chen X, Liu X, et al. MicroRNA-30d regulates cardiomyocyte pyroptosis by directly targeting foxo3a in diabetic cardiomyopathy. Cell Death Dis. 2014; 5:e1479.

127. León LE, Rani S, Fernandez M, Larico M, Calligaris SD. Subclinical detection of diabetic cardiomyopathy with microRNAs: challenges and perspectives. J Diabetes Res. 2016; 2016:6143129.

128. Kong Y, Tannous P, Lu G, Berenji K, Rothermel BA, Olson EN, et al. Suppression of class I and II histone deacetylases blunts pressure-overload cardiac hypertrophy. Circulation. 2006; 113:2579–2588.

129. Granger A, Abdullah I, Huebner F, Stout A, Wang T, Huebner T, et al. Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice. FASEB J. 2008; 22:3549–3560.

130. Chen Y, Du J, Zhao YT, Zhang L, Lv G, Zhuang S, et al. Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice. Cardiovasc Diabetol. 2015; 14:99.

131. Yu XY, Geng YJ, Liang JL, Lin QX, Lin SG, Zhang S, et al. High levels of glucose induce apoptosis in cardiomyocyte via epigenetic regulation of the insulin-like growth factor receptor. Exp Cell Res. 2010; 316:2903–2909.

132. Lee TI, Kao YH, Tsai WC, Chung CC, Chen YC, Chen YJ. HDAC inhibition modulates cardiac PPARs and fatty acid metabolism in diabetic cardiomyopathy. PPAR Res. 2016; 2016:5938740.

133. Yu XY, Geng YJ, Liang JL, Zhang S, Lei HP, Zhong SL, et al. High levels of glucose induce “metabolic memory” in cardiomyocyte via epigenetic histone H3 lysine 9 methylation. Mol Biol Rep. 2012; 39:8891–8898.

134. Koshelev M, Sarma S, Price RE, Wehrens XH, Cooper TA. Heart-specific overexpression of CUGBP1 reproduces functional and molecular abnormalities of myotonic dystrophy type 1. Hum Mol Genet. 2010; 19:1066–1075.

135. Wei C, Qiu J, Zhou Y, Xue Y, Hu J, Ouyang K, et al. Repression of the central splicing regulator RBFox2 is functionally linked to pressure overload-induced heart failure. Cell Reports. 2015; 10:1521–1533.

136. Verma SK, Deshmukh V, Liu P, Nutter CA, Espejo R, Hung ML, et al. Reactivation of fetal splicing programs in diabetic hearts is mediated by protein kinase C signaling. J Biol Chem. 2013; 288:35372–35386.

137. Nutter CA, Jaworski EA, Verma SK, Deshmukh V, Wang Q, Botvinnik OB, et al. Dysregulation of RBFOX2 is an early event in cardiac pathogenesis of diabetes. Cell Reports. 2016; 15:2200–2213.

138. Davidson SM, Yellon DM, Murphy MP, Duchen MR. Slow calcium waves and redox changes precede mitochondrial permeability transition pore opening in the intact heart during hypoxia and reoxygenation. Cardiovasc Res. 2012; 93:445–453.

139. Supinski GS, Murphy MP, Callahan LA. MitoQ administration prevents endotoxin-induced cardiac dysfunction. Am J Physiol Regul Integr Comp Physiol. 2009; 297:R1095–R1102.

140. Adlam VJ, Harrison JC, Porteous CM, James AM, Smith RA, Murphy MP, et al. Targeting an antioxidant to mitochondria decreases cardiac ischemia-reperfusion injury. FASEB J. 2005; 19:1088–1095.

141. Goh KY, He L, Song J, Jinno M, Rogers AJ, Sethu P, et al. Mitoquinone ameliorates pressure overload-induced cardiac fibrosis and left ventricular dysfunction in mice. Redox Biol. 2019; 21:101100.

142. Escribano-Lopez I, Diaz-Morales N, Rovira-Llopis S, de Marañon AM, Orden S, Alvarez A, et al. The mitochondria-targeted antioxidant MitoQ modulates oxidative stress, inflammation and leukocyte-endothelium interactions in leukocytes isolated from type 2 diabetic patients. Redox Biol. 2016; 10:200–205.

143. Frederick DW, Loro E, Liu L, Davila A Jr, Chellappa K, Silverman IM, et al. Loss of NAD homeostasis leads to progressive and reversible degeneration of skeletal muscle. Cell Metab. 2016; 24:269–282.

144. Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, et al. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 2016; 24:795–806.

145. Yoshino J, Mills KF, Yoon MJ, Imai S. Nicotinamide mononucleotide, a key NAD⁺ intermediate, treats the pathophysiology of diet- and age-induced diabetes in mice. Cell Metab. 2011; 14:528–536.

146. Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD⁺ in healthy middle-aged and older adults. Nat Commun. 2018; 9:1286.

147. Lee CF, Chavez JD, Garcia-Menendez L, Choi Y, Roe ND, Chiao YA, et al. Normalization of NAD⁺ redox balance as a therapy for heart failure. Circulation. 2016; 134:883–894.

148. Waldman M, Nudelman V, Shainberg A, Abraham NG, Kornwoski R, Aravot D, et al. PARP-1 inhibition protects the diabetic heart through activation of SIRT1-PGC-1α axis. Exp Cell Res. 2018; 373:112–118.

149. Sisay M, Edessa D. PARP inhibitors as potential therapeutic agents for various cancers: focus on niraparib and its first global approval for maintenance therapy of gynecologic cancers. Gynecol Oncol Res Pract. 2017; 4:18.

150. Zhao P, Zhang J, Yin XG, Maharaj P, Narraindoo S, Cui LQ, et al. The effect of trimetazidine on cardiac function in diabetic patients with idiopathic dilated cardiomyopathy. Life Sci. 2013; 92:633–638.

151. Maier LS, Layug B, Karwatowska-Prokopczuk E, Belardinelli L, Lee S, Sander J, et al. RAnoLazIne for the treatment of diastolic heart failure in patients with preserved ejection fraction: the RALI-DHF proof-of-concept study. JACC Heart Fail. 2013; 1:115–122.

152. Levelt E, Gulsin G, Neubauer S, McCann GP. MECHANISMS IN ENDOCRINOLOGY: Diabetic cardiomyopathy: pathophysiology and potential metabolic interventions state of the art review. Eur J Endocrinol. 2018; 178:R127–R139.

153. Lee L, Campbell R, Scheuermann-Freestone M, Taylor R, Gunaruwan P, Williams L, et al. Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment. Circulation. 2005; 112:3280–3288.

154. Beadle RM, Williams LK, Kuehl M, Bowater S, Abozguia K, Leyva F, et al. Improvement in cardiac energetics by perhexiline in heart failure due to dilated cardiomyopathy. JACC Heart Fail. 2015; 3:202–211.

155. Borghetti G, von Lewinski D, Eaton DM, Sourij H, Houser SR, Wallner M. Diabetic cardiomyopathy: current and future therapies. Beyond glycemic control. Front Physiol. 2018; 9:1514.

156. Kenny HC, Abel ED. Heart failure in type 2 diabetes mellitus. Circ Res. 2019; 124:121–141.