Abstract
Diabetes causes energy metabolism disturbance and may lead to cardiac dysfunction. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) protects cardiac function from myocardial damage. Therefore, understanding of its roles in diabetic heart is critical for developing new therapeutics targeting ALDH2 and mitochondrial function for diabetic hearts. This study investigated the impact of ALDH2 deficiency on diastolic function and energy metabolism in diabetic mice. Diabetes was induced in ALDH2 knockout and wild-type mice by streptozotocin. Cardiac function was determined by echocardiography. Glucose uptake, energy status, and metabolic profiles were used to evaluate cardiac energy metabolism. The association between ALDH2 polymorphism and diabetes was also analyzed in patients. Echocardiography revealed preserved systolic function and impaired diastolic function in diabetic ALDH2-deficient mice. Energy reserves (phosphocreatine/adenosine triphosphate ratio) were reduced in the diabetic mutants and were associated with diastolic dysfunction. Western blot analysis showed that diabetes induces accumulated lipid peroxidation products and escalated AMP-activated protein kinase–LKB1 pathway. Further, ALDH2 deficiency exacerbated the diabetes-induced deficient myocardial glucose uptake and other perturbations of metabolic profiles. Finally, ALDH2 mutations were associated with worse diastolic dysfunction in diabetic patients. Together, our results demonstrate that ALDH2 deficiency and resulting energy metabolism disturbance is a part of pathology of diastolic dysfunction of diabetic hearts, and suggest that patients with ALDH2 mutations are vulnerable to diabetic damage.
Key Message
-
ALDH2 deficiency exacerbates diastolic dysfunction in early diabetic hearts.
-
ALDH2 deficiency triggers decompensation of metabolic reserves and energy metabolism disturbances in early diabetic hearts.
-
ALDH2 deficiency potentiates oxidative stress and AMPK phosphorylation induced by diabetes via post-translational regulation of LKB1.
-
Diabetic patients with ALDH2 mutations are predisposed to worse diastolic dysfunction.
Similar content being viewed by others
References
Dhingra R, Vasan RS (2012) Diabetes and the risk of heart failure. Heart Fail Clin 8:125–133. doi: 10.1016/j.hfc.2011.08.008
Goyal BR, Mehta AA (2013) Diabetic cardiomyopathy: pathophysiological mechanisms and cardiac dysfuntion. Hum Exp Toxicol 32:571–590. doi: 10.1177/0960327112450885
Falcao-Pires I, Hamdani N, Borbely A, Gavina C, Schalkwijk CG, van der Velden J, van Heerebeek L, Stienen GJ, Niessen HW, Leite-Moreira AF, et al. (2011) Diabetes mellitus worsens diastolic left ventricular dysfunction in aortic stenosis through altered myocardial structure and cardiomyocyte stiffness. Circulation 124:1151–1159. doi: 10.1161/CIRCULATIONAHA.111.025270
Kruger M, Babicz K, von Frieling-Salewsky M, WA L (2010) Insulin signaling regulates cardiac titin properties in heart development and diabetic cardiomyopathy. J Mol Cell Cardiol 48:910–916. doi: 10.1016/j.yjmcc.2010.02.012.
Lovelock JD, Monasky MM, Jeong EM, Lardin HA, Liu H, Patel BG, Taglieri DM, Gu L, Kumar P, Pokhrel N, et al. (2012) Ranolazine improves cardiac diastolic dysfunction through modulation of myofilament calcium sensitivity. Circ Res 110:841–850. doi: 10.1161/CIRCRESAHA.111.258251
Mori J, Basu R, McLean BA, Das SK, Zhang L, Patel VB, Wagg CS, Kassiri Z, Lopaschuk GD, Oudit GY (2012) Agonist-induced hypertrophy and diastolic dysfunction are associated with selective reduction in glucose oxidation: a metabolic contribution to heart failure with normal ejection fraction. Circ Heart Fail 5:493–503. doi: 10.1161/CIRCHEARTFAILURE.112.966705
Fontes-Carvalho R, Ladeiras-Lopes R, Bettencourt P, Leite-Moreira A, Azevedo A (2015) Diastolic dysfunction in the diabetic continuum: association with insulin resistance, metabolic syndrome and type 2 diabetes. Cardiovasc Diabetol 14:4. doi: 10.1186/s12933-014-0168-x.
Guo Y, Yu W, Sun D, Wang J, Li C, Zhang R, Babcock SA, Li Y, Liu M, Ma M, et al. (2015) A novel protective mechanism for mitochondrial aldehyde dehydrogenase (ALDH2) in type I diabetes-induced cardiac dysfunction: role of AMPK-regulated autophagy. Biochim Biophys Acta 1852:319–331. doi: 10.1016/j.bbadis.2014.05.017
Zhang Y, Babcock SA, Hu N, Maris JR, Wang H, Ren J (2012) Mitochondrial aldehyde dehydrogenase (ALDH2) protects against streptozotocin-induced diabetic cardiomyopathy: role of GSK3beta and mitochondrial function. BMC Med 10:40. doi:10.1186/1741-7015-10-40
Shen C, Wang C, Fan F, Yang Z, Cao Q, Liu X, Sun X, Zhao X, Wang P, Ma X, et al. (2015) Acetaldehyde dehydrogenase 2 (ALDH2) deficiency exacerbates pressure overload-induced cardiac dysfunction by inhibiting Beclin-1 dependent autophagy pathway. Biochim Biophys Acta 1852:310–318. doi: 10.1016/j.bbadis.2014.07.014
Tseng LT, Lin CL, Tzen KY, Chang SC, Chang MF (2013) LMBD1 protein serves as a specific adaptor for insulin receptor internalization. J Biol Chem 288:32424–32432. doi: 10.1074/jbc.M113.479527
Sun A, Cheng Y, Zhang Y, Zhang Q, Wang S, Tian S, Zou Y, Hu K, Ren J, Ge J (2014) Aldehyde dehydrogenase 2 ameliorates doxorubicin-induced myocardial dysfunction through detoxification of 4-HNE and suppression of autophagy. J Mol Cell Cardiol 71:92–104. doi: 10.1016/j.yjmcc.2014.01.002
Zhang Y, Mi SL, Hu N, Doser TA, Sun A, Ge J, Ren J (2014) Mitochondrial aldehyde dehydrogenase 2 accentuates aging-induced cardiac remodeling and contractile dysfunction: role of AMPK, Sirt1, and mitochondrial function. Free Radic Biol Med 71:208–220. doi: 10.1016/j.freeradbiomed.2014.03.018
Spindler M, Saupe KW, Tian R, Ahmed S, Matlib MA, Ingwall JS (1999) Altered creatine kinase enzyme kinetics in diabetic cardiomyopathy. A(31)P NMR magnetization transfer study of the intact beating rat heart. J Mol Cell Cardiol 31:2175–2189. doi: 10.1006/jmcc.1999.1044
Grahame HD (2014) AMP-activated protein kinase: a key regulator of energy balance with many roles in human disease. J Intern Med 276:543–559. doi: 10.1111/joim.12268
McCarty MF (2014) AMPK activation—protean potential for boosting healthspan. Age (Dordr) 36:641–663. doi: 10.1007/s11357-013-9595-y
Gomes KM, Campos JC, Bechara LR, Queliconi B, Lima VM, Disatnik MH, Magno P, Chen CH, Brum PC, Kowaltowski AJ, et al. (2014) Aldehyde dehydrogenase 2 activation in heart failure restores mitochondrial function and improves ventricular function and remodelling. Cardiovasc Res 103:498–508. doi: 10.1093/cvr/cvu125
Rider OJ, Francis JM, Ali MK, Holloway C, Pegg T, Robson MD, Tyler D, Byrne J, Clarke K, Neubauer S (2012) Effects of catecholamine stress on diastolic function and myocardial energetics in obesity. Circulation 125:1511–1519. doi: 10.1161/CIRCULATIONAHA.111.069518
Neubauer S (2007) The failing heart—an engine out of fuel. N Engl J Med 356:1140–1151. doi: 10.1056/NEJMra063052
Neubauer S, Horn M, Cramer M, Harre K, Newell JB, Peters W, Pabst T, Ertl G, Hahn D, Ingwall JS, et al. (1997) Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation 96:2190–2196. doi: 10.1161/01.CIR.96.7.2190
Carley AN, Taegtmeyer H, Lewandowski ED (2014) Matrix revisited: mechanisms linking energy substrate metabolism to the function of the heart. Circ Res 114:717–729. 10.1161/CIRCRESAHA.114.301863
Shen W, Asai K, Uechi M, Mathier MA, Shannon RP, Vatner SF, Ingwall JS (1999) Progressive loss of myocardial ATP due to a loss of total purines during the development of heart failure in dogs: a compensatory role for the parallel loss of creatine. Circulation 100:2113–2118. doi: 10.1161/01.CIR.100.20.2113
Beer M, Seyfarth T, Sandstede J, Landschutz W, Lipke C, Kostler H, von Kienlin M, Harre K, Hahn D, Neubauer S (2002) Absolute concentrations of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with (31)P-SLOOP magnetic resonance spectroscopy. J Am Coll Cardiol 40:1267–1274. doi: 10.1016/S0735-1097(02)02160-5
Perseghin G, Lattuada G, De Cobelli F, Esposito A, Canu T, Ragogna F, Maffi P, Scifo P, Secchi A, Del MA, et al. (2012) Left ventricular function and energy homeostasis in patients with type 1 diabetes with and without microvascular complications. Int J Cardiol 154:111–115. doi: 10.1016/j.ijcard.2010.09.010
Maslov MY, Chacko VP, Hirsch GA, Akki A, Leppo MK, Steenbergen C, Weiss RG (2010) Reduced in vivo high-energy phosphates precede adriamycin-induced cardiac dysfunction. Am J Physiol Heart Circ Physiol 299:H332–H337. doi: 10.1152/ajpheart.00727.2009
Isfort M, Stevens SC, Schaffer S, Jong CJ, Wold LE (2014) Metabolic dysfunction in diabetic cardiomyopathy. Heart Fail Rev 19:35–48. doi: 10.1007/s10741-013-9377-8
Bodiga VL, Eda SR, Bodiga S (2014) Advanced glycation end products: role in pathology of diabetic cardiomyopathy. Heart Fail Rev 19:49–63. doi: 10.1007/s10741-013-9374-y
Sysi-Aho M, Ermolov A, Gopalacharyulu PV, Tripathi A, Seppanen-Laakso T, Maukonen J, Mattila I, Ruohonen ST, Vahatalo L, Yetukuri L, et al. (2011) Metabolic regulation in progression to autoimmune diabetes. PLoS Comput Biol 7:e1002257. doi: 10.1371/journal.pcbi.1002257
Christoffersen C, Bollano E, Lindegaard ML, Bartels ED, Goetze JP, Andersen CB, Nielsen LB (2003) Cardiac lipid accumulation associated with diastolic dysfunction in obese mice. Endocrinology 144:3483–3490. doi: 10.1210/en.2003-0242
Anderson EJ, Katunga LA, Willis MS (2012) Mitochondria as a source and target of lipid peroxidation products in healthy and diseased heart. Clin Exp Pharmacol Physiol 39:179–193. doi: 10.1111/j.1440-1681.2011.05641.x
Chapple SJ, Cheng X, Mann GE (2013) Effects of 4-hydroxynonenal on vascular endothelial and smooth muscle cell redox signaling and function in health and disease. Redox Biol 1:319–331. doi: 10.1016/j.redox.2013.04.001
Lim HY, Wang W, Wessells RJ, Ocorr K, Bodmer R (2011) Phospholipid homeostasis regulates lipid metabolism and cardiac function through SREBP signaling in drosophila. Genes Dev 25:189–200. doi: 10.1101/gad.1992411
Mourmoura E, Vial G, Laillet B, Rigaudiere JP, Hininger-Favier I, Dubouchaud H, Morio B, Demaison L (2013) Preserved endothelium-dependent dilatation of the coronary microvasculature at the early phase of diabetes mellitus despite the increased oxidative stress and depressed cardiac mechanical function ex vivo. Cardiovasc Diabetol 12:49. doi: 10.1186/1475-2840-12-49
Cheng S, Rhee EP, Larson MG, Lewis GD, McCabe EL, Shen D, Palma MJ, Roberts LD, Dejam A, Souza AL, et al. (2012) Metabolite profiling identifies pathways associated with metabolic risk in humans. Circulation 125:2222–2231. doi: 10.1161/CIRCULATIONAHA.111.067827
Ma W, JH W, Wang Q, Lemaitre RN, Mukamal KJ, Djousse L, King IB, Song X, Biggs ML, Delaney JA, et al. (2015) Prospective association of fatty acids in the de novo lipogenesis pathway with risk of type 2 diabetes: the cardiovascular health study. Am J Clin Nutr 101:153–163. doi: 10.3945/ajcn.114.092601
Liu Y, Yan X, Mao G, Fang L, Zhao B, Liu Y, Tang H, Wang N (2013) Metabonomic profiling revealed an alteration in purine nucleotide metabolism associated with cardiac hypertrophy in rats treated with thiazolidinediones. J Proteome Res 12:5634–5641. doi: 10.1021/pr400587y
Taylor DR, Alaghband-Zadeh J, Cross GF, Omar S, le Roux CW, Vincent RP (2014) Urine bile acids relate to glucose control in patients with type 2 diabetes mellitus and a body mass index below 30 kg/m2. PLoS One 9:e93540. doi: 10.1371/journal.pone.0093540
Wang G, Li W, Lu X, Zhao X (2011) Riboflavin alleviates cardiac failure in type I diabetic cardiomyopathy. Heart Int 6:e21. doi: 10.4081/hi.2011.e21
Katsumata Y, Shinmura K, Sugiura Y, Tohyama S, Matsuhashi T, Ito H, Yan X, Ito K, Yuasa S, Ieda M, et al. (2014) Endogenous prostaglandin D2 and its metabolites protect the heart against ischemia-reperfusion injury by activating Nrf2. Hypertension 63:80–87. doi: 10.1161/HYPERTENSIONAHA.113.01639
Oresic M (2012) Metabolomics in the studies of islet autoimmunity and type 1 diabetes. Rev Diabet Stud 9:236–247. doi: 10.1900/RDS.2012.9.236
Meikle PJ, Wong G, Barlow CK, Weir JM, Greeve MA, MacIntosh GL, Almasy L, Comuzzie AG, Mahaney MC, Kowalczyk A, et al. (2013) Plasma lipid profiling shows similar associations with prediabetes and type 2 diabetes. PLoS One 8:e74341. doi: 10.1371/journal.pone.0074341
Lee CH, Hung KC, Chang SH, Lin FC, Hsieh MJ, Chen CC, Chu CM, Hsieh IC, Wen MS, Wu D (2012) Reversible left ventricular diastolic dysfunction on Doppler tissue imaging predicts a more favorable prognosis in chronic heart failure. Circ J 76:1145–1150. doi: 10.1253/circj.CJ-11-0929
Loffredo FS, Nikolova AP, Pancoast JR, Lee RT (2014) Heart failure with preserved ejection fraction: molecular pathways of the aging myocardium. Circ Res 115:97–107. doi: 10.1161/CIRCRESAHA.115.302929
Li H, Borinskaya S, Yoshimura K, Kal’Ina N, Marusin A, Stepanov VA, Qin Z, Khaliq S, Lee MY, Yang Y, et al. (2009) Refined geographic distribution of the oriental ALDH2*504Lys (nee 487Lys) variant. Ann Hum Genet 73(Pt 3):335–345. doi: 10.1111/j.1469-1809.2009.00517.x
Chen CH, Ferreira JC, Gross ER, Mochly-Rosen D (2014) Targeting aldehyde dehydrogenase 2: new therapeutic opportunities. Physiol Rev 94:1–34. doi: 10.1152/physrev.00017.2013
Acknowledgment
The authors acknowledge Liming Wei (the Institute of Biomedical Science, Fudan University) for technical support. This work was supported by National Natural Science Foundation of China (81570224; 81521001).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
This study was carried out in accordance with the Guide for the Care and Use of Laboratory Animals, Eighth edition (2011). All procedures were approved by the Institutional Animal Care and Use Committee of Fudan University. The human polymorphism protocol was approved by Fudan University Ethics Committee and all participants provided informed consent for participation in accordance with the Declaration of Helsinki (World Medical Association and R281).
Conflict of interest
The authors declare no competing financial interests.
Additional information
Cong Wang, Fan Fan and Quan Cao contributed equally to this work.
Electronic supplementary material
ESM 1
(PDF 134 kb)
Rights and permissions
About this article
Cite this article
Wang, C., Fan, F., Cao, Q. et al. Mitochondrial aldehyde dehydrogenase 2 deficiency aggravates energy metabolism disturbance and diastolic dysfunction in diabetic mice. J Mol Med 94, 1229–1240 (2016). https://doi.org/10.1007/s00109-016-1449-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00109-016-1449-5