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Diabetologia
Published in: Diabetologia 4/2014

01-04-2014 | Review

Molecular mechanisms of diabetic cardiomyopathy

Authors: Heiko Bugger, E. Dale Abel

Published in: Diabetologia | Issue 4/2014

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Abstract

In recent years, diabetes mellitus has become an epidemic and now represents one of the most prevalent disorders. Cardiovascular complications are the major cause of mortality and morbidity in diabetic patients. While ischaemic events dominate the cardiac complications of diabetes, it is widely recognised that the risk for developing heart failure is also increased in the absence of overt myocardial ischaemia and hypertension or is accelerated in the presence of these comorbidities. These diabetes-associated changes in myocardial structure and function have been called diabetic cardiomyopathy. Numerous molecular mechanisms have been proposed to contribute to the development of diabetic cardiomyopathy following analysis of various animal models of type 1 or type 2 diabetes and in genetically modified mouse models. The steady increase in reports presenting novel mechanistic data on this subject expands the list of potential underlying mechanisms. The current review provides an update on molecular alterations that may contribute to the structural and functional alterations in the diabetic heart.
Literature
1.
2.
Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman A (1972) New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 30:595–602PubMed
3.
de Simone G, Devereux RB, Chinali M et al (2010) Diabetes and incident heart failure in hypertensive and normotensive participants of the Strong Heart Study. J Hypertens 28:353–360PubMedCentralPubMed
4.
Litwin SE (2013) Diabetes and the heart: is there objective evidence of a human diabetic cardiomyopathy? Diabetes 62:3329–3330PubMed
5.
Devereux RB, Roman MJ, Paranicas M et al (2000) Impact of diabetes on cardiac structure and function: the Strong Heart Study. Circulation 101:2271–2276PubMed
6.
Lee M, Gardin JM, Lynch JC et al (1997) Diabetes mellitus and echocardiographic left ventricular function in free-living elderly men and women: the Cardiovascular Health Study. Am Heart J 133:36–43PubMed
7.
Kannel WB, McGee DL (1979) Diabetes and cardiovascular disease. The Framingham study. JAMA 241:2035–2038PubMed
8.
Boyer JK, Thanigaraj S, Schechtman KB, Perez JE (2004) Prevalence of ventricular diastolic dysfunction in asymptomatic, normotensive patients with diabetes mellitus. Am J Cardiol 93:870–875PubMed
9.
Shivalkar B, Dhondt D, Goovaerts I et al (2006) Flow mediated dilatation and cardiac function in type 1 diabetes mellitus. Am J Cardiol 97:77–82PubMed
10.
Fang ZY, Schull-Meade R, Leano R, Mottram PM, Prins JB, Marwick TH (2005) Screening for heart disease in diabetic subjects. Am Heart J 149:349–354PubMed
11.
Ernande L, Bergerot C, Rietzschel ER et al (2011) Diastolic dysfunction in patients with type 2 diabetes mellitus: is it really the first marker of diabetic cardiomyopathy? J Am Soc Echocardiogr 24:1268–1275PubMed
12.
Bugger H, Abel ED (2009) Rodent models of diabetic cardiomyopathy. Dis Model Mech 2:454–466PubMed
13.
Wu KK, Huan Y (2007) Diabetic atherosclerosis mouse models. Atherosclerosis 191:241–249PubMed
14.
Goldin A, Beckman JA, Schmidt AM, Creager MA (2006) Advanced glycation end products: sparking the development of diabetic vascular injury. Circulation 114:597–605PubMed
15.
Norton GR, Candy G, Woodiwiss AJ (1996) Aminoguanidine prevents the decreased myocardial compliance produced by streptozotocin-induced diabetes mellitus in rats. Circulation 93:1905–1912PubMed
16.
Aragno M, Mastrocola R, Medana C et al (2006) Oxidative stress-dependent impairment of cardiac-specific transcription factors in experimental diabetes. Endocrinology 147:5967–5974PubMed
17.
Bidasee KR, Zhang Y, Shao CH et al (2004) Diabetes increases formation of advanced glycation end products on Sarco(endo)plasmic reticulum Ca2+ -ATPase. Diabetes 53:463–473PubMed
18.
Kranstuber AL, del Rio C, Biesiadecki BJ et al (2012) Advanced glycation end product cross-link breaker attenuates diabetes-induced cardiac dysfunction by improving sarcoplasmic reticulum calcium handling. Front Physiol 3:292PubMedCentralPubMed
19.
Ma H, Li SY, Xu P et al (2009) Advanced glycation endproduct (AGE) accumulation and AGE receptor (RAGE) up-regulation contribute to the onset of diabetic cardiomyopathy. J Cell Mol Med 13:1751–1764PubMedCentralPubMed
20.
Regan TJ, Lyons MM, Ahmed SS et al (1977) Evidence for cardiomyopathy in familial diabetes mellitus. J Clin Invest 60:884–899PubMed
21.
Shimizu M, Umeda K, Sugihara N et al (1993) Collagen remodelling in myocardia of patients with diabetes. J Clin Pathol 46:32–36PubMedCentralPubMed
22.
Westermann D, Rutschow S, Jager S et al (2007) Contributions of inflammation and cardiac matrix metalloproteinase activity to cardiac failure in diabetic cardiomyopathy: the role of angiotensin type 1 receptor antagonism. Diabetes 56:641–646PubMed
23.
Singh VP, Le B, Khode R, Baker KM, Kumar R (2008) Intracellular angiotensin II production in diabetic rats is correlated with cardiomyocyte apoptosis, oxidative stress, and cardiac fibrosis. Diabetes 57:3297–3306PubMedCentralPubMed
24.
Mizushige K, Yao L, Noma T et al (2000) Alteration in left ventricular diastolic filling and accumulation of myocardial collagen at insulin-resistant prediabetic stage of a type II diabetic rat model. Circulation 101:899–907PubMed
25.
Chiu J, Farhangkhoee H, Xu BY, Chen S, George B, Chakrabarti S (2008) PARP mediates structural alterations in diabetic cardiomyopathy. J Mol Cell Cardiol 45:385–393PubMed
26.
Van Linthout S, Seeland U, Riad A et al (2008) Reduced MMP-2 activity contributes to cardiac fibrosis in experimental diabetic cardiomyopathy. Basic Res Cardiol 103:319–327PubMed
27.
Diamant M, Lamb HJ, Smit JW, de Roos A, Heine RJ (2005) Diabetic cardiomyopathy in uncomplicated type 2 diabetes is associated with the metabolic syndrome and systemic inflammation. Diabetologia 48:1669–1670PubMed
28.
Tschope C, Walther T, Escher F et al (2005) Transgenic activation of the kallikrein-kinin system inhibits intramyocardial inflammation, endothelial dysfunction and oxidative stress in experimental diabetic cardiomyopathy. FASEB J 19:2057–2059PubMed
29.
Westermann D, Rutschow S, van Linthout S et al (2006) Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus. Diabetologia 49:2507–2513PubMed
30.
Westermann D, van Linthout S, Dhayat S et al (2007) Cardioprotective and anti-inflammatory effects of interleukin converting enzyme inhibition in experimental diabetic cardiomyopathy. Diabetes 56:1834–1841PubMed
31.
Rajesh M, Batkai S, Kechrid M et al (2012) Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy. Diabetes 61:716–727PubMedCentralPubMed
32.
Westermann D, van Linthout S, Dhayat S et al (2007) Tumor necrosis factor-alpha antagonism protects from myocardial inflammation and fibrosis in experimental diabetic cardiomyopathy. Basic Res Cardiol 102:500–507PubMed
33.
Westermann D, Walther T, Savvatis K et al (2009) Gene deletion of the kinin receptor B1 attenuates cardiac inflammation and fibrosis during the development of experimental diabetic cardiomyopathy. Diabetes 58:1373–1381PubMedCentralPubMed
34.
35.
Rajesh M, Mukhopadhyay P, Batkai S et al (2009) Xanthine oxidase inhibitor allopurinol attenuates the development of diabetic cardiomyopathy. J Cell Mol Med 13:2330–2341PubMedCentralPubMed
36.
Li J, Zhu H, Shen E, Wan L, Arnold JM, Peng T (2010) Deficiency of rac1 blocks NADPH oxidase activation, inhibits endoplasmic reticulum stress, and reduces myocardial remodeling in a mouse model of type 1 diabetes. Diabetes 59:2033–2042PubMedCentralPubMed
37.
Jadhav A, Tiwari S, Lee P, Ndisang JF (2013) The heme oxygenase system selectively enhances the anti-inflammatory macrophage-M2 phenotype, reduces pericardial adiposity, and ameliorated cardiac injury in diabetic cardiomyopathy in Zucker diabetic fatty rats. J Pharmacol Exp Ther 345:239–249PubMed
38.
Ti Y, Xie GL, Wang ZH et al (2011) TRB3 gene silencing alleviates diabetic cardiomyopathy in a type 2 diabetic rat model. Diabetes 60:2963–2974PubMedCentralPubMed
39.
Monji A, Mitsui T, Bando YK, Aoyama M, Shigeta T, Murohara T (2013) Glucagon-like peptide-1 receptor activation reverses cardiac remodeling via normalizing cardiac steatosis and oxidative stress in type 2 diabetes. Am J Physiol 305:H295–H304
40.
Frustaci A, Kajstura J, Chimenti C et al (2000) Myocardial cell death in human diabetes. Circ Res 87:1123–1132PubMed
41.
Cai L, Li W, Wang G, Guo L, Jiang Y, Kang YJ (2002) Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes 51:1938–1948PubMed
42.
Huynh K, Kiriazis H, Du XJ et al (2013) Targeting the upregulation of reactive oxygen species subsequent to hyperglycemia prevents type 1 diabetic cardiomyopathy in mice. Free Radic Biol Med 60:307–317PubMed
43.
Varma A, Das A, Hoke NN, Durrant DE, Salloum FN, Kukreja RC (2012) Anti-inflammatory and cardioprotective effects of tadalafil in diabetic mice. PLoS One 7:e45243PubMedCentralPubMed
44.
Chowdhry MF, Vohra HA, Galinanes M (2007) 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 134:124–131PubMed
45.
Sari FR, Watanabe K, Thandavarayan RA et al (2010) 14-3-3 protein protects against cardiac endoplasmic reticulum stress (ERS) and ERS-initiated apoptosis in experimental diabetes. J Pharmacol Sci 113:325–334PubMed
46.
Ares-Carrasco S, Picatoste B, Benito-Martin A et al (2009) Myocardial fibrosis and apoptosis, but not inflammation, are present in long-term experimental diabetes. Am J Physiol Heart Circ Physiol 297:H2109–H2119PubMed
47.
Bojunga J, Nowak D, Mitrou PS, Hoelzer D, Zeuzem S, Chow KU (2004) Antioxidative treatment prevents activation of death-receptor- and mitochondrion-dependent apoptosis in the hearts of diabetic rats. Diabetologia 47:2072–2080PubMed
48.
Kajstura J, Fiordaliso F, Andreoli AM et al (2001) IGF-1 overexpression inhibits the development of diabetic cardiomyopathy and angiotensin II-mediated oxidative stress. Diabetes 50:1414–1424PubMed
49.
Andrabi SA, Dawson TM, Dawson VL (2008) Mitochondrial and nuclear cross talk in cell death: parthanatos. Ann N Y Acad Sci 1147:233–241PubMed
50.
Puthanveetil P, Zhang D, Wang Y et al (2012) Diabetes triggers a PARP1 mediated death pathway in the heart through participation of FoxO1. J Mol Cell Cardiol 53:677–686PubMed
51.
Orea-Tejeda A, Colin-Ramirez E, Castillo-Martinez L et al (2007) Aldosterone receptor antagonists induce favorable cardiac remodeling in diastolic heart failure patients. Rev Invest Clin 59:103–107PubMed
52.
Brown L, Wall D, Marchant C, Sernia C (1997) Tissue-specific changes in angiotensin II receptors in streptozotocin-diabetic rats. J Endocrinol 154:355–362PubMed
53.
Li SY, Yang X, Ceylan-Isik AF, Du M, Sreejayan N, Ren J (2006) Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch. Diabetologia 49:1434–1446PubMed
54.
Fauconnier J, Lanner JT, Zhang SJ et al (2005) Insulin and inositol 1,4,5-trisphosphate trigger abnormal cytosolic Ca2+ transients and reveal mitochondrial Ca2+ handling defects in cardiomyocytes of ob/ob mice. Diabetes 54:2375–2381PubMed
55.
Van den Bergh A, Vanderper A, Vangheluwe P et al (2008) Dyslipidaemia in type II diabetic mice does not aggravate contractile impairment but increases ventricular stiffness. Cardiovasc Res 77:371–379PubMed
56.
Belke DD, Swanson EA, Dillmann WH (2004) Decreased sarcoplasmic reticulum activity and contractility in diabetic db/db mouse heart. Diabetes 53:3201–3208PubMed
57.
Pereira L, Matthes J, Schuster I et al (2006) Mechanisms of [Ca2+]i transient decrease in cardiomyopathy of db/db type 2 diabetic mice. Diabetes 55:608–615PubMed
58.
Ye G, Metreveli NS, Ren J, Epstein PN (2003) Metallothionein prevents diabetes-induced deficits in cardiomyocytes by inhibiting reactive oxygen species production. Diabetes 52:777–783PubMed
59.
Ye G, Metreveli NS, Donthi RV et al (2004) Catalase protects cardiomyocyte function in models of type 1 and type 2 diabetes. Diabetes 53:1336–1343PubMed
60.
Kralik PM, Ye G, Metreveli NS, Shem X, Epstein PN (2005) Cardiomyocyte dysfunction in models of type 1 and type 2 diabetes. Cardiovasc Toxicol 5:285–292PubMed
61.
Lopaschuk GD, Tahiliani AG, Vadlamudi RV, Katz S, McNeill JH (1983) Cardiac sarcoplasmic reticulum function in insulin- or carnitine-treated diabetic rats. Am J Physiol Heart Circ Physiol 245:H969–H976
62.
Flarsheim CE, Grupp IL, Matlib MA (1996) Mitochondrial dysfunction accompanies diastolic dysfunction in diabetic rat heart. Am J Physiol Heart Circ Physiol 271:H192–H202
63.
Bugger H, Abel ED (2008) Molecular mechanisms for myocardial mitochondrial dysfunction in the metabolic syndrome. Clin Sci (Lond) 114:195–210
64.
Pereira RO, Wende AR, Olsen C et al (2013) Inducible overexpression of GLUT1 prevents mitochondrial dysfunction and attenuates structural remodeling in pressure overload but does not prevent left ventricular dysfunction. J Am Heart Assoc 2:e000301PubMedCentralPubMed
65.
Luo M, Guan X, Luczak ED et al (2013) Diabetes increases mortality after myocardial infarction by oxidizing CaMKII. J Clin Invest 123:1262–1274PubMedCentralPubMed
66.
Erickson JR, Pereira L, Wang L et al (2013) Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation. Nature 502:372–376PubMed
67.
Bugger H, Boudina S, Hu XX et al (2008) Type 1 diabetic akita mouse hearts are insulin sensitive but manifest structurally abnormal mitochondria that remain coupled despite increased uncoupling protein 3. Diabetes 57:2924–2932PubMedCentralPubMed
68.
Buchanan J, Mazumder PK, Hu P et al (2005) Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology 146:5341–5349PubMed
69.
Peterson LR, Herrero P, Schechtman KB et al (2004) Effect of obesity and insulin resistance on myocardial substrate metabolism and efficiency in young women. Circulation 109:2191–2196PubMed
70.
Finck BN, Lehman JJ, Leone TC et al (2002) The cardiac phenotype induced by PPARalpha overexpression mimics that caused by diabetes mellitus. J Clin Invest 109:121–130PubMedCentralPubMed
71.
Gibbs EM, Stock JL, McCoid SC et al (1995) Glycemic improvement in diabetic db/db mice by overexpression of the human insulin-regulatable glucose transporter (GLUT4). J Clin Invest 95:1512–1518PubMedCentralPubMed
72.
Belke DD, Larsen TS, Gibbs EM, Severson DL (2000) Altered metabolism causes cardiac dysfunction in perfused hearts from diabetic (db/db) mice. Am J Physiol Endocrinol Metab 279:E1104–E1113PubMed
73.
Wright JJ, Kim J, Buchanan J et al (2009) Mechanisms for increased myocardial fatty acid utilization following short-term high-fat feeding. Cardiovasc Res 82:351–360PubMedCentralPubMed
74.
Mazumder PK, O’Neill BT, Roberts MW et al (2004) Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts. Diabetes 53:2366–2374PubMed
75.
Boudina S, Sena S, Theobald H et al (2007) Mitochondrial energetics in the heart in obesity-related diabetes: direct evidence for increased uncoupled respiration and activation of uncoupling proteins. Diabetes 56:2457–2466PubMed
76.
Boudina S, Sena S, O’Neill BT, Tathireddy P, Young ME, Abel ED (2005) Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impair myocardial energetics in obesity. Circulation 112:2686–2695PubMed
77.
Echtay KS, Roussel D, St-Pierre J et al (2002) Superoxide activates mitochondrial uncoupling proteins. Nature 415:96–99PubMed
78.
Yagyu H, Chen G, Yokoyama M et al (2003) Lipoprotein lipase (LpL) on the surface of cardiomyocytes increases lipid uptake and produces a cardiomyopathy. J Clin Invest 111:419–426PubMedCentralPubMed
79.
80.
Chiu HC, Kovacs A, Blanton RM et al (2005) Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy. Circ Res 96:225–233PubMed
81.
Rijzewijk LJ, van der Meer RW, Smit JW et al (2008) Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J Am Coll Cardiol 52:1793–1799PubMed
82.
Son NH, Yu S, Tuinei J et al (2010) PPARγ-induced cardiolipotoxicity in mice is ameliorated by PPARα deficiency despite increases in fatty acid oxidation. J Clin Invest 120:3443–3454PubMedCentralPubMed
83.
Zhou YT, Grayburn P, Karim A et al (2000) Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci U S A 97:1784–1789PubMedCentralPubMed
84.
Lee Y, Naseem RH, Park BH et al (2006) Alpha-lipoic acid prevents lipotoxic cardiomyopathy in acyl CoA-synthase transgenic mice. Biochem Biophys Res Commun 344:446–452PubMed
85.
Lee Y, Naseem RH, Duplomb L et al (2004) Hyperleptinemia prevents lipotoxic cardiomyopathy in acyl CoA synthase transgenic mice. Proc Natl Acad Sci U S A 101:13624–13629PubMedCentralPubMed
86.
Listenberger LL, Ory DS, Schaffer JE (2001) Palmitate-induced apoptosis can occur through a ceramide-independent pathway. J Biol Chem 276:14890–14895PubMed
87.
Ostrander DB, Sparagna GC, Amoscato AA, McMillin JB, Dowhan W (2001) Decreased cardiolipin synthesis corresponds with cytochrome c release in palmitate-induced cardiomyocyte apoptosis. J Biol Chem 276:38061–38067PubMed
88.
Borradaile NM, Han X, Harp JD, Gale SE, Ory DS, Schaffer JE (2006) Disruption of endoplasmic reticulum structure and integrity in lipotoxic cell death. J Lipid Res 47:2726–2737PubMed
89.
Brookheart RT, Michel CI, Listenberger LL, Ory DS, Schaffer JE (2009) The non-coding RNA gadd7 is a regulator of lipid-induced oxidative and endoplasmic reticulum stress. J Biol Chem 284:7446–7454PubMedCentralPubMed
90.
Michel CI, Holley CL, Scruggs BS et al (2011) Small nucleolar RNAs U32a, U33, and U35a are critical mediators of metabolic stress. Cell Metab 14:33–44PubMedCentralPubMed
91.
Anderson EJ, Kypson AP, Rodriguez E, Anderson CA, Lehr EJ, Neufer PD (2009) Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart. J Am Coll Cardiol 54:1891–1898PubMedCentralPubMed
92.
Anderson EJ, Rodriguez E, Anderson CA, Thayne K, Chitwood WR, Kypson AP (2011) Increased propensity for cell death in diabetic human heart is mediated by mitochondrial-dependent pathways. Am J Physiol Heart Circ Physiol 300:H118–H124PubMedCentralPubMed
93.
Kuo TH, Giacomelli F, Wiener J (1985) Oxidative metabolism of Polytron versus Nagarse mitochondria in hearts of genetically diabetic mice. Biochim Biophys Acta 806:9–15PubMed
94.
Konig A, Bode C, Bugger H (2012) Diabetes mellitus and myocardial mitochondrial dysfunction: bench to bedside. Heart Fail Clin 8:551–561PubMed
95.
Cook SA, Varela-Carver A, Mongillo M et al (2010) Abnormal myocardial insulin signalling in type 2 diabetes and left-ventricular dysfunction. Eur Heart J 31:100–111PubMedCentralPubMed
96.
Shimizu I, Minamino T, Toko H et al (2010) Excessive cardiac insulin signaling exacerbates systolic dysfunction induced by pressure overload in rodents. J Clin Invest 120:1506–1514PubMedCentralPubMed
97.
Fullmer TM, Pei S, Zhu Y et al (2013) Insulin suppresses ischemic preconditioning-mediated cardioprotection through Akt-dependent mechanisms. J Mol Cell Cardiol 64:20–29PubMed
98.
Battiprolu PK, Hojayev B, Jiang N et al (2012) Metabolic stress-induced activation of FoxO1 triggers diabetic cardiomyopathy in mice. J Clin Invest 122:1109–1118PubMedCentralPubMed
99.
Boudina S, Bugger H, Sena S et al (2009) Contribution of impaired myocardial insulin signaling to mitochondrial dysfunction and oxidative stress in the heart. Circulation 119:1272–1283PubMedCentralPubMed
100.
Bugger H, Riehle C, Jaishy B et al (2012) Genetic loss of insulin receptors worsens cardiac efficiency in diabetes. J Mol Cell Cardiol 52:1019–1026PubMedCentralPubMed
101.
Wallace DC (1992) Mitochondrial genetics: a paradigm for aging and degenerative diseases? Science 256:628–632PubMed
102.
Lashin OM, Szweda PA, Szweda LI, Romani AM (2006) Decreased complex II respiration and HNE-modified SDH subunit in diabetic heart. Free Radic Biol Med 40:886–896PubMed
103.
Turko IV, Li L, Aulak KS, Stuehr DJ, Chang JY, Murad F (2003) Protein tyrosine nitration in the mitochondria from diabetic mouse heart. Implications to dysfunctional mitochondria in diabetes. J Biol Chem 278:33972–33977PubMed
104.
Shen X, Zheng S, Metreveli NS, Epstein PN (2006) Protection of cardiac mitochondria by overexpression of MnSOD reduces diabetic cardiomyopathy. Diabetes 55:798–805PubMed
105.
Herlein JA, Fink BD, O’Malley Y, Sivitz WI (2009) Superoxide and respiratory coupling in mitochondria of insulin-deficient diabetic rats. Endocrinology 150:46–55PubMedCentralPubMed
106.
Serpillon S, Floyd BC, Gupte RS et al (2009) 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 297:H153–H162PubMedCentralPubMed
107.
Wold LE, Ceylan-Isik AF, Fang CX et al (2006) Metallothionein alleviates cardiac dysfunction in streptozotocin-induced diabetes: role of Ca2+ cycling proteins, NADPH oxidase, poly(ADP-Ribose) polymerase and myosin heavy chain isozyme. Free Radic Biol Med 40:1419–1429PubMed
108.
Levine B, Klionsky DJ (2004) Development by self-digestion: molecular mechanisms and biological functions of autophagy. Dev Cell 6:463–477PubMed
109.
Nakai A, Yamaguchi O, Takeda T et al (2007) The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress. Nat Med 13:619–624PubMed
110.
Yan L, Vatner DE, Kim SJ et al (2005) Autophagy in chronically ischemic myocardium. Proc Natl Acad Sci U S A 102:13807–13812PubMedCentralPubMed
111.
Zhu H, Tannous P, Johnstone JL et al (2007) Cardiac autophagy is a maladaptive response to hemodynamic stress. J Clin Invest 117:1782–1793PubMedCentralPubMed
112.
Matsui Y, Takagi H, Qu X et al (2007) Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res 100:914–922PubMed
113.
114.
Riehle C, Wende AR, Sena S et al (2013) Insulin receptor substrate signaling suppresses neonatal autophagy in the heart. J Clin Invest 123:5319–5333PubMedCentralPubMed
115.
Troncoso R, Vicencio JM, Parra V et al (2012) Energy-preserving effects of IGF-1 antagonize starvation-induced cardiac autophagy. Cardiovasc Res 93:320–329PubMedCentralPubMed
116.
Mellor KM, Bell JR, Young MJ, Ritchie RH, Delbridge LM (2011) Myocardial autophagy activation and suppressed survival signaling is associated with insulin resistance in fructose-fed mice. J Mol Cell Cardiol 50:1035–1043PubMed
117.
Zhao J, Brault JJ, Schild A et al (2007) FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab 6:472–483PubMed
118.
Hausenloy DJ, Mocanu MM, Yellon DM (2004) Cross-talk between the survival kinases during early reperfusion: its contribution to ischemic preconditioning. Cardiovasc Res 63:305–312PubMed
119.
Sala-Mercado JA, Wider J, Undyala VV et al (2010) Profound cardioprotection with chloramphenicol succinate in the swine model of myocardial ischemia-reperfusion injury. Circulation 122:S179–S184PubMedCentralPubMed
120.
Nemchenko A, Chiong M, Turer A, Lavandero S, Hill JA (2011) Autophagy as a therapeutic target in cardiovascular disease. J Mol Cell Cardiol 51:584–593PubMedCentralPubMed
121.
Mellor KM, Reichelt ME, Delbridge LM (2011) Autophagy anomalies in the diabetic myocardium. Autophagy 7:1263–1267PubMed
122.
Xie Z, Lau K, Eby B et al (2011) Improvement of cardiac functions by chronic metformin treatment is associated with enhanced cardiac autophagy in diabetic OVE26 mice. Diabetes 60:1770–1778PubMedCentralPubMed
123.
Kornfeld JW, Baitzel C, Konner AC et al (2013) Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b. Nature 494:111–115PubMed
124.
Jordan SD, Kruger M, Willmes DM et al (2011) Obesity-induced overexpression of miRNA-143 inhibits insulin-stimulated AKT activation and impairs glucose metabolism. Nat Cell Biol 13:434–446PubMed
125.
Zhou B, Li C, Qi W et al (2012) Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity. Diabetologia 55:2032–2043PubMed
126.
Trajkovski M, Hausser J, Soutschek J et al (2011) MicroRNAs 103 and 107 regulate insulin sensitivity. Nature 474:649–653PubMed
127.
Chen JF, Murchison EP, Tang R et al (2008) Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure. Proc Natl Acad Sci U S A 105:2111–2116PubMedCentralPubMed
128.
Feng B, Chen S, George B, Feng Q, Chakrabarti S (2010) miR133a regulates cardiomyocyte hypertrophy in diabetes. Diabetes Metab Res Rev 26:40–49PubMed
129.
Kartha RV, Subramanian S (2010) MicroRNAs in cardiovascular diseases: biology and potential clinical applications. J Cardiovasc Transl Res 3:256–270PubMed
130.
Katare R, Caporali A, Zentilin L et al (2011) Intravenous gene therapy with PIM-1 via a cardiotropic viral vector halts the progression of diabetic cardiomyopathy through promotion of prosurvival signaling. Circ Res 108:1238–1251PubMed
131.
Xiao J, Luo X, Lin H et al (2007) MicroRNA miR-133 represses HERG K+ channel expression contributing to QT prolongation in diabetic hearts. J Biol Chem 282:12363–12367PubMed
132.
Duisters RF, Tijsen AJ, Schroen B et al (2009) miR-133 and miR-30 regulate connective tissue growth factor: implications for a role of microRNAs in myocardial matrix remodeling. Circ Res 104:170–178PubMed
133.
Bentwich I, Avniel A, Karov Y et al (2005) Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet 37:766–770PubMed
134.
Friedman RC, Farh KK, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105PubMedCentralPubMed
135.
Khan O, La Thangue NB (2012) HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol Cell Biol 90:85–94PubMed
136.
McKinsey TA (2011) Isoform-selective HDAC inhibitors: closing in on translational medicine for the heart. J Mol Cell Cardiol 51:491–496PubMed
137.
Chuang DM, Leng Y, Marinova Z, Kim HJ, Chiu CT (2009) Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends Neurosci 32:591–601PubMedCentralPubMed
138.
Chang S, McKinsey TA, Zhang CL, Richardson JA, Hill JA, Olson EN (2004) Histone deacetylases 5 and 9 govern responsiveness of the heart to a subset of stress signals and play redundant roles in heart development. Mol Cell Biol 24:8467–8476PubMedCentralPubMed
139.
Hamamori Y, Schneider MD (2003) HATs off to Hop: recruitment of a class I histone deacetylase incriminates a novel transcriptional pathway that opposes cardiac hypertrophy. J Clin Invest 112:824–826PubMedCentralPubMed
140.
Gaikwad AB, Sayyed SG, Lichtnekert J, Tikoo K, Anders HJ (2010) Renal failure increases cardiac histone h3 acetylation, dimethylation, and phosphorylation and the induction of cardiomyopathy-related genes in type 2 diabetes. Am J Pathol 176:1079–1083PubMedCentralPubMed
141.
Monkemann H, de Vriese AS, Blom HJ et al (2002) Early molecular events in the development of the diabetic cardiomyopathy. Amino Acids 23:331–336PubMed
142.
Kuan CJ, al-Douahji M, Shankland SJ (1998) The cyclin kinase inhibitor p21WAF1, CIP1 is increased in experimental diabetic nephropathy: potential role in glomerular hypertrophy. J Am Soc Nephrol 9:986–993PubMed
143.
Kaneto H, Kajimoto Y, Fujitani Y et al (1999) Oxidative stress induces p21 expression in pancreatic islet cells: possible implication in beta-cell dysfunction. Diabetologia 42:1093–1097PubMed
144.
Li Z, Zhang T, Dai H et al (2007) Involvement of endoplasmic reticulum stress in myocardial apoptosis of streptozocin-induced diabetic rats. J Clin Biochem Nutr 41:58–67PubMedCentralPubMed
145.
Xu J, Wang G, Wang Y et al (2009) Diabetes- and angiotensin II-induced cardiac endoplasmic reticulum stress and cell death: metallothionein protection. J Cell Mol Med 13:1499–1512PubMed
146.
Lakshmanan AP, Harima M, Suzuki K et al (2013) 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 45:438–447PubMed
147.
Liu ZW, Zhu HT, Chen KL et al (2013) Protein kinase RNA- like endoplasmic reticulum kinase (PERK) signaling pathway plays a major role in reactive oxygen species (ROS)-mediated endoplasmic reticulum stress-induced apoptosis in diabetic cardiomyopathy. Cardiovasc Diabetol 12:158PubMed
148.
Liu J, Liu Y, Chen L, Wang Y, Li J (2013) Glucagon-like peptide-1 analog liraglutide protects against diabetic cardiomyopathy by the inhibition of the endoplasmic reticulum stress pathway. J Diabetes Res 2013:630537PubMedCentralPubMed
149.
Younce CW, Burmeister MA, Ayala JE (2013) 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–C518PubMed
Metadata
Title
Molecular mechanisms of diabetic cardiomyopathy
Authors
Heiko Bugger
E. Dale Abel
Publication date
01-04-2014
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 4/2014
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-014-3171-6

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