Uncoupling protein 2 regulates myocardial apoptosis via the diabetogenic action of streptozotocin

Xiu-Zhen Li, Ruo-Yun Tan, Xiang Lu

.

DOI: 10.4236/jbise.2011.47064                

Abstract

Objective: Determine the role of uncoupling protein 2 (UCP2) in the myocardial apoptosis of diabetic mellitus（DM）. Methods: DM animal models were induced by streptozotocinon (STZ) on UCP2 knock-out mice (UCP2KO) and wild-type mice (WT), which were reared for 7 and 28 days after successful modeling, respectively. The expressions of relative protein for myocardial apoptosis, pro-caspase-9, were investigated using western blot. However, the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) was used to explain apoptosis at the DNA level. Results: Image analysis showed that the expression of pro-caspase-9 protein levels increased slightly in UCP-/- + DM-7-day group comparing with DM-7-day group (P > 0.05). The expression of pro-caspase-9 protein levels increased significantly (P < 0.05）in UCP-/- + DM-28-day group comparing with DM-28-day group. TUNEL analysis indicated that UCP2 reduced the number of apoptotic myocytes in the DM-28-day group by 70% in comparison to DM-7-day group by 30% (P < 0.05). Conclusion UCP2 may be one of the most important factors that contribute to the myocardial apoptosis of DM.

Keywords

Uncoupling Protein 2; Diabetes; Myocardium; Apoptosis

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Ricquier, D. and Bouillaud, F. (2000) The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. Biochemical Journal, 345, 161-179. doi:10.1042/0264-6021:3450161
[2]	Blanc, J., Alves-Guerra, M.C., Esposito, B., et al. (2003) Protective role of uncoupling protein 2 in atherosclerosis. Circulation, 107, 388-390. doi:10.1161/01.CIR.0000051722.66074.60
[3]	Chan, C.B., Saleh, M.C., Koshkin, V., et al. (2004) Uncoupling protein 2 and islet function. Diabetes, 53, 136-142. doi:10.2337/diabetes.53.2007.S136
[4]	Arsenijevic, D., Onuma, H., Pecqueur, C., et al. (2000) Disruption of the uncoupling protein-2 gene in mice reveals a role in immunity and reactive oxygen species production. Nature Genetics, 26, 435-439. doi:10.1038/82565
[5]	Teshima, Y., Akao, M., Jones, S.P., et al. (2003) Uncoupling protein-2 overexpression inhibits mitochondrial death pathway in cardiomyocytes circulation research. Circulation Research, 93, 192-200。 doi:10.1161/01.RES.0000085581.60197.4D
[6]	Brand, M.D., Buckingham, J.A., Esteves, T.C., et al. (2004) Mitochondrial superoxide and aging: Uncoupling-protein activity and superoxide production. Biochemical Society Symposia, 71, 203-213.
[7]	Zhang, C., Baffy, G., Perret, P., et al. (2001) Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, β-cell dysfunction, and type2 diabetes. Cell, 105, 745-755. doi:10.1016/S0092-8674(01)00378-6
[8]	King, L.M., Sidell, R.J., Wilding, J.R., Radda, G.K. and Clarke, K. (2001) Free fatty acids, but not ketone bodies, protect diabetic rat hearts during low-?ow ischemia. American Journal of Physiology—Heart and Circulatory Physiology, 280, H1173-H1181.
[9]	Li, Z.H., Zhang, T., Dai, H.Y., et al. (2007) Involvement of endoplasmic reticulum stress in myocardial apoptosis of streptozocin-induced diabetic rats. Journal of Clinical Biochemistry and Nutrition, 41, 58-67. doi:10.3164/jcbn.2007008
[10]	Devereux, R.B., Roman, M.J., Paranicas, M., et al. (2000) Impact of diabetes on cardiac structure and function: The strong heart study. Circulation, 101, 2271-2276.
[11]	Rubler, S., Dlugash, J., Yuceoglu, Y.Z., et al. (1997) New type of cardiomyopathy associated with diabetic Glomerulosclerosis. American Journal of Cardiology, 30, 595-602.
[12]	doi:10.1016/0002-9149(72)90595-4
[13]	Wei, X.X., Zhou, X.P., He, D., et al. (1992) Cardiac disease in streptozocin-induced diabetes. Chinese Journal of Endocrinology and Metabolism, 4, 222-225.
[14]	Cai, L., Wang, Y., Zhou, G., et al. (2006) Attenuation by metallothionein of early cardiac cell death via suppression of mitochondrial oxidative stress results in a prevention of diabetic cardiomyopathy. Journal of the American College of Cardiology, 48, 1688-1697. doi:10.1016/j.jacc.2006.07.022
[15]	Sung, P.H., Sun, C.K., Ko, S.F., et al. (2009) Impact of hyperglycemic control on left ventricular myocardium a molecular and cellular basic study in a diabetic rat mode. International Heart Journal, 50, 191-206. doi:10.1536/ihj.50.191
[16]	Li, C.Y., Cao, L.S., Zeng, Q.T., et al. (2005) Taurine may prevent diabetic rats from developing cardiomyopathy also by down regulating angiotensinⅡtype-2 receptor expression. Cardiovascular Drugs and Therapy, 19, 105-112. doi:10.1007/s10557-005-0443-x
[17]	Joseph, J.W., Koshkin, V., Zhang, C.Y., et al. (2002) Uncoupling protein 2 knockout mice have enhanced insulin secretary capacity after a high-fat diet. Diabetes, 51, 3211-3219. doi:10.2337/diabetes.51.11.3211
[18]	Joseph, J.W., Koshkin, V., Saleh, M.C., et al. (2004) Free fatty acid-induced beta-cell defects are dependent on uncoupling protein 2 expressions. The Journal of Biological Chemistry, 279, 51049-51056. doi:10.1074/jbc.M409189200
[19]	Arsenijevic, D., Onuma, H., Pecqueur, C., et al. (2000) Disruption of the uncoupling protein gene in mice reveals a role in immunity and reactive oxygen species production. Nature Genetics, 26, 435-439. doi:10.1038/82565
[20]	Lee, S.C., Robson-Doucette, C.A. and Wheeler, M.B. (2009) Uncoupling protein 2 regulates reactive oxygen species formation in islets and influences susceptibility to diabetogenic action of streptozotocin. Journal of Endocrinology, 203, 33-43. doi:10.1677/JOE-09-0117
[21]	Andrews, Z.B. and Horvath, T. (2009) Uncoupling protein-2 regulates lifespan in mice. American Journal of Physiology—Endocrinology and Metabolism, 296, E621-E627. doi:10.1152/ajpendo.90903.2008