Ayhan TANYELİ, Metin BAŞTUĞ, Derya GÜZEL ERDOĞAN, Ali Doğan DURSUN, Fırat AKAT, Hakan FIÇICILAR

Deneysel Tip 1 Diabetes Mellitusta Aralıklı Hipoksinin Kardiyak Kas Kalsiyum Homeostazına Etkisi

Amaç: Bu çalışmada; deneysel diyabetik kardiyomiyopatide intermittan hipoksinin kardiyak fosfolamban ve CaMKII düzeylerine etkisi araştırıldı.

Anahtar Kelimeler:

Diabetik Kardiyomyopati, Aralıklı hipoksi

Effect Of Intermittent Hypoxia On Cardiac Muscle Calcium Homeostasis In Experimental Type 1 Diabetes Mellitus

Purpose: In this study; it was investigated the effect of intermittent hypoxia on cardiac phospholamban and CaMKII levels in experimental diabetic cardiomyopathy. Material and method:Wistar albino male rats (n=34) were randomized to four groups: control (C), intermittent hypoxia (IH), diabetes mellitus (DM) and diabetes mellitus + intermittent hypoxia (DM+IH). Injection of streptozotocin (50 mg/kg, i.p.) followed by 250 mg/dL and above blood glucose levels , was accepted as diabetes mellitus. The IH and DM+IH groups were subjected to 6 hours/day hypoxia for 42 days at a pressure corresponding to a height of 3000 m. 24 hours after the IH protocol was completed, the hearts of the animals were removed. Phospholamban and CaMKII were conducted by agarose gel electrophoresis method after polymerase chain reaction. After the images were obtained with a UV camera; band density was determined in the Image J program. The resulting data were compared with the Kruskal Wallis test, multiple comparisons tests, and the Wilcoxon test. Results:When the rates of the increasing weight of the experimental animals were examined, it was observed that the weight increase in the IH group was at most and the DM group was at least. The differences between C and DM (p=0.003), C to DM+IH (p=0.024), IH to DM (p=0.001), IH to DM+IH (p=0.006) groups were statistically meaningful at the end of the experiment. It has not been detected any meaningful difference among the groups of PLB/GAPDH (p=0.294). In terms of CaMKII/GAPDH, a statistically significant difference was found between C and DM; C and DM+IH and IH and DM+IH groups (p<0.05). Conclusion:Our study suggests that CaMKII has a role in diabetic cardiomyopathy in detecting differences in CaMKII level. However, changes in the phospholamban have not been detected, but are important in the effects of translational and/or posttranslational levels and in the changes that may occur in protein levels and/or activations.

Keywords:

Diabetic Cardiomyopathy,

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1. Boudina, S. and E.D. Abel, Diabetic cardiomyopathy revisited. Circulation, 2007. 115(25): p. 3213-23.
2. Falcao-Pires, I. and A.F. Leite-Moreira, Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment. Heart Fail Rev, 2012. 17(3): p. 325-44.
3. Liu, J.E., et al., The impact of diabetes on left ventricular filling pattern in normotensive and hypertensive adults: the Strong Heart Study. J Am Coll Cardiol, 2001. 37(7): p. 1943-9.
4. Cai, Z., et al., Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury. Circulation, 2003. 108(1): p. 79-85.
5. Milano, G., et al., Chronic and intermittent hypoxia induce different degrees of myocardial tolerance to hypoxia-induced dysfunction. Exp Biol Med (Maywood), 2002. 227(6): p. 389-97.
6. Yu, Z., Z.H. Wang, and H.T. Yang, Calcium/calmodulin-dependent protein kinase II mediates cardioprotection of intermittent hypoxia against ischemic-reperfusion-induced cardiac dysfunction. Am J Physiol Heart Circ Physiol, 2009. 297(2): p. H735-42.
7. Xie, Y., et al., Role of dual-site phospholamban phosphorylation in intermittent hypoxia-induced cardioprotection against ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol, 2005. 288(6): p. H2594-602.
8. Muhm, J.M., et al., Effect of aircraft-cabin altitude on passenger discomfort. N Engl J Med, 2007. 357(1): p. 18-27.
9. Tuncay, E., et al., ss-blocker timolol prevents arrhythmogenic Ca(2)(+) release and normalizes Ca(2)(+) and Zn(2)(+) dyshomeostasis in hyperglycemic rat heart. PLoS One, 2013. 8(7): p. e71014.
10. Mp, G., et al., Antidiabetic potential of cow urine in streptozotocin- induced diabetic rats. Asian J ‎Tradit Med, 2010. 6.
11. Naghshin, J., et al., Chronic intermittent hypoxia increases left ventricular contractility in C57BL/6J mice. J Appl Physiol (1985), 2009. 107(3): p. 787-93.
12. Abeeleh, M., et al., Induction of Diabetes Mellitus in Rats Using Intraperitoneal Streptozotocin: A Comparison between 2 Strains of Rats. European Journal of Scientific Research, 2009. 32: p. 398-402.
13. M., Z., Diabetes mellitus and high altitude. Diabetologia Croatica, 2001. 30:: p. 23-28.
14. Anderson, J.D. and B. Honigman, The effect of altitude-induced hypoxia on heart disease: do acute, intermittent, and chronic exposures provide cardioprotection? High Alt Med Biol, 2011. 12(1): p. 45-55.
15. Mirit, E., et al., Changes in cardiac mechanics with heat acclimation: adrenergic signaling and SR-Ca regulatory proteins. Am J Physiol Regul Integr Comp Physiol, 2000. 279(1): p. R77-85.
16. Schworer, C.M., et al., Identification of novel isoforms of the delta subunit of Ca2+/calmodulin-dependent protein kinase II. Differential expression in rat brain and aorta. J Biol Chem, 1993. 268(19): p. 14443-9.
17. Joffe, II, et al., Abnormal cardiac function in the streptozotocin-induced non-insulin-dependent diabetic rat: noninvasive assessment with doppler echocardiography and contribution of the nitric oxide pathway. J Am Coll Cardiol, 1999. 34(7): p. 2111-9.
18. Hoit, B.D., et al., Noninvasive evaluation of cardiac dysfunction by echocardiography in streptozotocin-induced diabetic rats. J Card Fail, 1999. 5(4): p. 324-33.
19. Trost, S.U., et al., Overexpression of the sarcoplasmic reticulum Ca(2+)-ATPase improves myocardial contractility in diabetic cardiomyopathy. Diabetes, 2002. 51(4): p. 1166-71.
20. Zhao, X.Y., et al., Decreased cardiac sarcoplasmic reticulum Ca2+ -ATPase activity contributes to cardiac dysfunction in streptozotocin-induced diabetic rats. J Physiol Biochem, 2006. 62(1): p. 1-8.
21. Kim, H.W., et al., Diabetic alterations in cardiac sarcoplasmic reticulum Ca2+-ATPase and phospholamban protein expression. Life Sci, 2001. 70(4): p. 367-79.
22. Netticadan, T., et al., Depressed levels of Ca2+-cycling proteins may underlie sarcoplasmic reticulum dysfunction in the diabetic heart. Diabetes, 2001. 50(9): p. 2133-8.
23. Vasanji, Z., N.S. Dhalla, and T. Netticadan, Increased inhibition of SERCA2 by phospholamban in the type I diabetic heart. Mol Cell Biochem, 2004. 261(1-2): p. 245-9.
24. Zhong, Y., et al., Altered SR protein expression associated with contractile dysfunction in diabetic rat hearts. Am J Physiol Heart Circ Physiol, 2001. 281(3): p. H1137-47.
25. Tuncay, E., E.N. Zeydanli, and B. Turan, Cardioprotective effect of propranolol on diabetes-induced altered intracellular Ca2+ signaling in rat. J Bioenerg Biomembr, 2011. 43(6): p. 747-56.
26. Hattori, Y., et al., Diminished function and expression of the cardiac Na+-Ca2+ exchanger in diabetic rats: implication in Ca2+ overload. J Physiol, 2000. 527 Pt 1: p. 85-94.
27. Kashihara, H., et al., Effects of diabetes and hypertension on myocardial Na+-Ca2+ exchange. Can J Physiol Pharmacol, 2000. 78(1): p. 12-9.
28. Bedoya, F.J., F. Solano, and M. Lucas, N-monomethyl-arginine and nicotinamide prevent streptozotocin-induced double strand DNA break formation in pancreatic rat islets. Experientia, 1996. 52(4): p. 344-7.
29. Howe, C.J., et al., Redox regulation of the calcium/calmodulin-dependent protein kinases. J Biol Chem, 2004. 279(43): p. 44573-81.
30. Zhu, W., et al., Activation of CaMKIIdeltaC is a common intermediate of diverse death stimuli-induced heart muscle cell apoptosis. J Biol Chem, 2007. 282(14): p. 10833-9.
31. Wagner, S., et al., Reactive oxygen species-activated Ca/calmodulin kinase IIdelta is required for late I(Na) augmentation leading to cellular Na and Ca overload. Circ Res, 2011. 108(5): p. 555-65.
32. Yeung, H.M., et al., Chronic intermittent hypoxia alters Ca2+ handling in rat cardiomyocytes by augmented Na+/Ca2+ exchange and ryanodine receptor activities in ischemia-reperfusion. Am J Physiol Cell Physiol, 2007. 292(6): p. C2046-56.
33. Bekeredjian, R., et al., Conditional HIF-1alpha expression produces a reversible cardiomyopathy. PLoS One, 2010. 5(7): p. e11693.
34. Chen, L., et al., Intermittent hypoxia protects cardiomyocytes against ischemia-reperfusion injury-induced alterations in Ca2+ homeostasis and contraction via the sarcoplasmic reticulum and Na+/Ca2+ exchange mechanisms. Am J Physiol Cell Physiol, 2006. 290(4): p. C1221-9.
35. Yuan, G., et al., Ca2+/calmodulin kinase-dependent activation of hypoxia inducible factor 1 transcriptional activity in cells subjected to intermittent hypoxia. J Biol Chem, 2005. 280(6): p. 4321-8.
36. Czibik, G., Complex role of the HIF system in cardiovascular biology. J Mol Med (Berl), 2010. 88(11): p. 1101-11.