Diabetes mellitus can cause cardiomyopathy disorders by inducing the aging pathway

Document Type : Original Article


1 Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

2 Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

3 Vascular and Endovascular surgery research center, Mashhad Medical university,Mashhad,Iran

4 Solid Tumor Research Center, Research Institute for Cellular and Molecular Medicine, Urmia University of Medical Sciences, Urmia, Iran


Objective(s): In this study, cardiovascular disorders were examined with a focus on the aging pathway and autophagy involvement in cardiac samples isolated from male rats with type 2 diabetes mellitus.
Materials and Methods: In the present study, male Wistar rats became diabetic with the help of a high-fat diet. Gene and protein expression levels (to evaluate Tumor Necrosis Factor-α, TNF-α) were measured by the ELISA method. Nrf2, p38, and GSK-3β proteins in cardiac tissue samples were measured by the western blotting method. Autophagy examination was performed with immunofluorescence staining. Finally, quantitative results were calculated using statistical analysis.
Results: The expression of beta-galactosidase genes had a significant increase in the diabetic group (P=0.0001). However, there was no significant difference in the expression of the SERCA2a gene between the diabetic and control groups. In terms of protein expression, the amount of TNF-α protein in the diabetic group was significantly different from that of the control group (P=0.0102). The expression levels of p38, Nrf2, and GSK-3β proteins increased compared with the control group. The use of the LC3 immunofluorescence staining technique revealed that autophagy increased in the diabetic group.
Conclusion: Type 2 diabetes mellitus in rats will increase aging in cardiac cells. Examination of the signaling pathway indicates that this effect is related to the increase of ROS and the activity of the signaling pathway. In response, the cardiac cells try to maintain their homeostasis by increasing autophagy and decreasing inflammatory cytokines.


1. Rawshani A, Rawshani A, Franzén S, Eliasson B, Svensson A-M, Miftaraj M, et al. Mortality and cardiovascular disease in type 1 and type 2 diabetes. N  Engl J Med 2017; 376:1407-1418.
2. Moucheraud C, Lenz C, Latkovic M, Wirtz VJ. The costs of diabetes treatment in low-and middle-income countries: a systematic review. BMJ Global Health 2019; 4: e001258.
3. yi Wong EL, Xu RH, ling Cheung AW. Measurement of health-related quality of life in patients with diabetes mellitus using EQ-5D-5L in Hong Kong, China. Qual Life Res 2020:29:1913-1921.
4. Ryden L, Ferrannini G, Mellbin L. Risk factor reduction in type 2 diabetes demands a multifactorial approach. Eur  j Prev Cardiol 2019;26:81-91.
5. Murtaza G, Virk HUH, Khalid M, Lavie CJ, Ventura H, Mukherjee D, et al. Diabetic cardiomyopathy-A comprehensive updated review. Prog Cardiovasc Dis 2019; 62:315-326.
6. Parim B, Uddandrao VS, Saravanan G. Diabetic cardiomyopathy: molecular mechanisms, detrimental effects of conventional treatment and beneficial effects of natural therapy. Heart Fail Rev 2019;24:279-299.
7. Bualeong T, Wyss JM, Roysommuti S. Inhibition of renin-angiotensin system from conception to young mature life induces salt-sensitive hypertension via angiotensin ii-induced sympathetic overactivity in adult male rats. Adv Exp Med Biol 2019. 45-59.
8. Salazar G. NADPH oxidases and mitochondria in vascular senescence. Int J Mol Sci 2018;19:1327-1360.
9. Manzo V. Anti-oxidative and antisenescent effects of cardiac rehabilitation in heart failure patients. 2016.
10. Yun HR, Jo YH, Kim J, Shin Y, Kim SS, Choi TG. Roles of autophagy in oxidative stress. Int J Mol Sci 2020;21:3289-3335.
11. Cho KH, Joo JI, Shin D, Kim D, Park SM. The reverse control of irreversible biological processes. Wiley Interdiscip Rev Syst  Biol Med 2016;8:366-377.
12. Patel TP, Rawal K, Bagchi AK, Akolkar G, Bernardes N, da Silva Dias D, et al. Insulin resistance: An additional risk factor in the pathogenesis of cardiovascular disease in type 2 diabetes. Heart Fail Rev 2016;21:11-23.
13. Hou X, Li Z, Higashi Y, Delafontaine P, Sukhanov S. Insulin-like growth factor i prevents cellular aging via activation of mitophagy. J  Aging Res 2020: 4939310.
14. Abdellatif M, Sedej S, Carmona-Gutierrez D, Madeo F, Kroemer G. Autophagy in cardiovascular aging. Circ Res 2018;123:803-824.
15. Giorgi C, Marchi S, Pinton P. The machineries, regulation and cellular functions of mitochondrial calcium. Nat Rev Mol Cell Biol 2018; 19:713-730.
16. Lombardi AA, Gibb AA, Arif E, Kolmetzky DW, Tomar D, Luongo TS, et al. Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation. Nat Commun 2019; 10:4509-4541.
17. Chung YJ, Luo A, Park KC, Loonat AA, Lakhal-Littleton S, Robbins PA, et al. Iron-deficiency anemia reduces cardiac contraction by downregulating RyR2 channels and suppressing SERCA pump activity. JCI insight 2019;4: e125618.
18. Franceschi C, Garagnani P, Morsiani C, Conte M, Santoro A, Grignolio A, et al. The continuum of aging and age-related diseases: common mechanisms but different rates. Front Med 2018; 5:61.
19. Fomison-Nurse IC. The Impact of Renal Denervation on Structural Changes of Diabetic Nephropathy: University of Otego; 2019.
20. Ryder JR, Northrop E, Rudser KD, Kelly AS, Gao Z, Khoury PR, et al. Accelerated early vascular aging among adolescents with obesity and/or type 2 diabetes mellitus. J Am Heart Assoc 2020;9:e014891.
21. Johnson SC, Sangesland M, Kaeberlein M, Rabinovitch PS. Modulating mTOR in aging and health. Aging and health-A systems biology perspective. 40: Karger Publishers; 2015;40:107-127.
22. Elfawy HA, Das B. Crosstalk between mitochondrial dysfunction, oxidative stress, and age related neurodegenerative disease: Etiologies and therapeutic strategies. Life Sci 2019;218:165-184.
23. Taneike M, Yamaguchi O, Nakai A, Hikoso S, Takeda T, Mizote I, et al. Inhibition of autophagy in the heart induces age-related cardiomyopathy. Autophagy 2010;6:600-606.
24. Hua Y, Zhang Y, Ceylan-Isik AF, Wold LE, Nunn JM, Ren J. Chronic Akt activation accentuates aging-induced cardiac hypertrophy and myocardial contractile dysfunction: Role of autophagy. Basic Res cardiol 2011;106:1173-1191.
25. Chang K, Kang P, Liu Y, Huang K, Miao T, Sagona AP, et al. TGFB-INHB/activin signaling regulates agedependent autophagy and cardiac health through inhibition of MTORC2. Autophagy 2019 ;16:1807-1822.
26. Humphrey JD. Cardiovascular solid mechanics: cells, tissues, and organs: Springer Science & Business Media;2013.
27. Cao Y, Chen J, Ren G, Zhang Y, Tan X, Yang L. Punicalagin prevents inflammation in LPS-Induced RAW264. 7 macrophages by inhibiting FoxO3a/autophagy signaling pathway. Nutrients 2019; 11:2794-2811.
28. Sun Y. Myocardial repair/remodelling following infarction: roles of local factors. Cardiovasc Res 2009;81:482-490.
29. Natali A, Nesti L, Fabiani I, Calogero E, Di Bello V. Impact of empagliflozin on subclinical left ventricular dysfunctions and on the mechanisms involved in myocardial disease progression in type 2 diabetes: Rationale and design of the EMPA-HEART trial. Cardiovasc Diabetol 2017;16:130-153.