Cardiac fibrosis and down regulation of GLUT4 in experimental diabetic cardiomyopathy are ameliorated by chronic exposures to intermittent altitude

Mahdi Faramoushi, Ramin Amir Sasan, Vahid Sari Sarraf, Pouran Karimi, Mahdi Faramoushi, Ramin Amir Sasan, Vahid Sari Sarraf, Pouran Karimi

Abstract

Introduction: Chronic intermittent hypoxia is considered as a preconditioning status in cardiovascular health to inducing resistance to the low oxygen supply. Diabetic cardiomyopathy leads to inability of the heart to effective circulation of blood preventing of consequent tissue damages so; the aim of this study was elucidation of effect of chronic exposure to hypoxia on Cardiac fibrosis and expression of GLUT4 in experimental diabetic cardiomyopathy.

Methods: A total number of 30 rats were randomly divided into three groups; 1: Normoxia control group (NN, n = 10). 2: Normoxia diabetic group (ND, n = 10) that took fat diet for 2 weeks then were injected by streptozotocin (37 mg/kg) and 3: Hypoxia diabetic group (HD, n = 10): that were exposed to chronic intermittent hypoxia (CIH) (altitude ≈3400 m, 14% oxygen for 8 weeks). After hypoxia challenge, plasma metabolic parameters including: fasting blood glucose (FBS), triglyceride (TG) and total cholesterol (TC) were measured by colorimetric assay. Cardiac expression of GLUT4 protein and cardiac collagen accumulation were determined in the excised left ventricle by western blotting, and Masson trichrome staining respectively.

Results: Based on resultant data, FBS, TG and TC were significantly (P < 0.05) decreased in HD vs. ND. Homeostasis Model Assessment (HOMA) were also significantly attenuated after exposed to CIH in HD group compared to ND group (P < 0.05). Significant increase in packed cell volume and hemoglobin concentration was observed in HD group compared to ND group (P < 0.05). Comparison of heart wet weight between three groups showed a significant difference (P < 0.05) with lower amount in HD and ND versus NN. Myocardial fibrosis was significantly more pronounced in ND when compared to NN. Eight weeks exposure to hypoxia ameliorated this increase in HD group. Intermittent hypoxia significantly increased GLUT4 protein expression in HD compared to ND group (P < 0.05).

Conclusion: Data suggested that CIH might potentiate to improve glucose homeostasis and cardiac tissue structural damages created in type 2 diabetes (T2D).

Keywords: Altitude; Cardiac; Cardiomyopathy; Fibrosis; GLUT4.

Figures

Figure 1
Figure 1
Figure 2
Figure 2

References

    1. Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010;87(1):4–14. doi: 10.1016/j.diabres.2009.10.007.
    1. Farag YM, Gaballa MR. Diabesity: an overview of a rising epidemic. Nephrol Dial Transplant. 2011;26(1):28–35. doi: 10.1093/ndt/gfq576‏.
    1. Rubler S, Dlugash J, Yuceoglu YZ, Kumral T, Branwood AW, Grishman G. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol. 1972;30(6):595–602 ‏.
    1. Gaster M, Staehr P, Beck-Nielsen H, Schrøder HD, Handberg A. GLUT4 is reduced in slow muscle fibers of type 2 diabetic patients: is insulin resistance in type 2 diabetes a slow, type 1 fiber disease? Diabetes. 2001;50(6):1324–1329‏. doi: 10.2337/diabetes.50.6.1324.
    1. MacLean PS, Zheng D, Dohm GL. Muscle glucose transporter (GLUT 4) gene expression during exercise. Exerc Sport Sci Rev. 2000;28:148–152‏.
    1. Mu J, Brozinick JT Jr, Valladares O, Bncan M, Birnbaum MJ. A role for AMP-activated pro- tein kinase in contraction- and hypoxia-regu- lated glucose transport in skeletal muscle. Mol Cell. 2001;7(5):1085–1094‏. doi: 10.1016/S1097-2765(01)00251-9.
    1. Somaratne JB, Whalley GA, Poppe KK, ter Bals MM, Wadams G, Pearl A. et al. screening for left ventricular hypertrophy in patients with type 2 diabetes mellitus in the community. Cardiovasc Diabetol. 2011;10:29‏. doi: 10.1186/1475-2840-10-29.
    1. Zibadi S, Cordova F, Slack EH, Watson RR, Larson DF. Leptin’s regulation of obesity-induced cardiac extracellular matrix remodeling. Cardiovasc Toxicol. 2011;11(4):325–333‏. doi: 10.1007/s12012-011-9124-0.
    1. Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation. 2007;115(25):3213–3223‏. doi: 10.1161/CIRCULATIONAHA.106.679597.
    1. Lin YM, Huang SK, Wang HF, Chen LM, Tsai FJ, Hsu HH. et al. Short-term versus long-term intermittent hypobaric hypoxia on cardiac fibrosis and fas death receptor dependent apoptotic pathway in rat hearts. Chin J Physiol. 2008;51(5):308–316‏.
    1. Virues-Ortega J, Hogan AM, Baya-Botti A, Kirkham FJ, Baldeweg T, Mahillo-Fernandez I. et al. Survival and mortality in older adults living at high altitude in Bolivia: a preliminary report. Am Geriatr Soc. 2009;57(10):1955–1956‏. doi: 10.1111/j.1532-5415.2009.02468.x.
    1. Duennwald T, Gatterer H, Groop PH, Burtscher M, Bernardi L. Effects of a single bout of interval hypoxia on cardiorespiratory control and blood glucose in patients with type 2 diabetes. Diabetes Care. 2013;36(8):2183–2189‏. doi: 10.2337/dc12-2113.
    1. Winkelmayer WC, Hurley MP, Liu J, Brookhart MA. Altitude and the risk of cardiovascular events in incident US dialysis patients. Nephrol Dial Transpl. 2012;27(6):2411–2417‏. doi: 10.1093/ndt/gfr681.
    1. Voors AW, Johnson WD. Altitude and arteriosclerotic heart disease mortality in white residents of 99 of the 100 largest cities in the United States. J Chronic Dis. 1979;32(1-2):157–162‏.
    1. Ezzati M, Horwitz ME, Thomas DS, Friedman AB, Roach R, Clark T. et al. Altitude, life expectancy and mortality from ischaemic heart disease, stroke, COPD and cancers: national population-based analysis of US counties Health. J Epidemiol Community Health. 2012;66(7):e17‏. doi: 10.1136/jech.2010.112938.
    1. Faeh D, Gutzwiller F, Bopp M . Swiss National Cohort Study Group . Lower mortality from coronary heart disease and stroke at higher altitudes in Switzerland. Circulation. 2009;120(6):495–501‏. doi: 10.1161/CIRCULATIONAHA.108.819250.
    1. Murray AJ. Metabolic adaptation of skeletal muscle to high altitude hypoxia: how new technologies could resolve the controversies. Genome Med. 2009;1(12):117‏. doi: 10.1186/gm117.
    1. Thangarajah H, Vial IN, Grogan RH, Yao D, Shi Y, Januszyk M. et al. HIF-1α dysfunction in diabetes. Cell Cycle. 2010;9(1):75–79‏. doi: 10.4161/cc.9.1.10371.
    1. Grijalva J, Hicks S, Zhao X, Medikayala S, Kaminski PM, Wolin MS. et al. ‘Exercise training enhanced myocardial endothelial nitric oxide synthase (eNOS) function in diabetic Goto-Kakizaki (GK) rats,’. Cardiovasc Diabetol. 2008;7:34. doi: 10.1186/1475-2840-7-34.
    1. Dill RP, Chadan SG, Li C, Parkhouse WS. Aging and glucose transporter plasticity in response to hypobaric hypoxia. Mech Ageing Dev. 2001;122(6):533–545. doi: 10.1016/S0047-6374(01)00216-0.
    1. Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P. Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res. 2005;52(4):313–320‏. doi: 10.1016/j.phrs.2005.05.004.
    1. Chiu LL, Chou SW, Cho YM, Ho HY, Ivy JL, Hunt D. et al. Effect of prolonged intermittent hypoxia and exercise training on glucose tolerance and muscle GLUT4 protein expression in rats. J Biomed Sci. 2004;11(6):838–846‏. doi: 10.1007/BF02254369.
    1. Mackenzie R, Maxwell N, Castle P, Elliott B, Brickley G, Watt P. Intermittent exercise with and without hypoxia improves insulin sensitivity in individuals with type 2 diabetes. J Clin Endocrinol Metab. 2012;97(4):E546–555‏. doi: 10.1210/jc.2011-2829.
    1. Chou SW, Chiu LL, Cho YM, Ho HY, Ivy JL, Ho CF. et al. Effect of systemic hypoxia on GLUT4 protein expression in exercised rat heart. Jpn J Physiol. 2004;54(4):357–363 ‏. doi: 10.2170/jjphysiol.54.357.
    1. Li J, Miller EJ, Ninomiya-Tsuji J, Russell RR 3rd, Young LH. AMP-activated protein kinase activates p38 mitogen-activated protein kinase by increasing recruitment of p38 MAPK to TAB1 in the ischemic heart. Circ Res. 2005;97(9):872–879‏. doi: 10.1161/01.RES.0000187458.77026.10.
    1. Chen YC, Lee SD, Kuo CH, Ho LT. The Effects of Altitude Training on the AMPK-Related Glucose Transport Pathway in the Red Skeletal Muscle of both Lean and Obese Zucker Rats. High Alt Med Biol. 2011;12(4):371–378‏. doi: 10.1089/ham.2010.1088.
    1. Nielsen JN, Jørgensen SB, Frøsig C, Viollet B, Andreelli F, Vaulont S. et al. A possible role for AMP-activated protein kinase in exercise-induced glucose utilization: insights from humans and transgenic animals. Biochem Soc Trans. 2003;31(Pt 1):186–190.
    1. Li J, Grigoryev DN, Ye SQ, Thorne L, Schwartz AR, Smith PL. et al. Chronic intermittent hypoxia upregulates genes of lipid biosynthesis in obese mice. J Appl Physiol. 2005;99(5):1643–1648‏.
    1. Huynh K, Bernardo BC, McMullen JR, Ritchie RH. Diabetic Cardiomyopathy: Mechanisms and New Treatment Strategies Targeting Antioxidant Signaling Pathways. Pharmacol Ther. 2014;142(3):375–415‏. doi: 10.1016/j.pharmthera.2014.01.003.
    1. Van de Weijer T, Schrauwen-Hinderling VB, Schrauwen P. Lipotoxicity in type 2 diabetic cardiomyopathy. Cardiovasc Res. 2011;92(1):10–18‏. doi: 10.1093/cvr/cvr212.
    1. Dei Cas A, Spigoni V, Ridolfi V, Metra M. Diabetes and chronic heart failure: from diabetic cardiomyopathy to therapeutic approach. Endocr Metab Immune Disord Drug Targets. 2013;13(1):38–50‏.
    1. Poornima IG, Parikh F, Shannon RF. Diabetic cardiomyopathy: The search for a unifying hypothesis. Circ Res. 2006;98:596–605. doi: 10.2174/1871530311313010006.
    1. Fuentes-Antrás J, Picatoste B, Gómez-Hernández A, Egido J, Tuñón J, Lorenzo Ó. Updating Experimental Models of Diabetic Cardiomyopathy. J Diabetes Res. 2015;2015:‏ 656795. doi: 10.1155/2015/656795.
    1. Prabhakar NR, Semenza GL. Adaptive and Maladaptive Cardiorespiratory Responses to Continuous and Intermittent Hypoxia Mediated by Hypoxia-Inducible Factors 1 and 2. 2012;92(3):967–1003‏. doi: 10.1152/physrev.00030.2011.
    1. Bertrand L, Horman S, Beauloye C, Vanoverschelde JL. Insulin signalling in the heart. Cardiovasc Res. 2008;79:238–248‏. doi: 10.1093/cvr/cvn093.
    1. Radovits T, Oláh A, Lux Á, Németh BT, Hidi L, Birtalan E. et al. Rat model of exercise-induced cardiac hypertrophy: hemodynamic characterization using left ventricular pressure-volume analysis. Am J Physiol Heart Circ Phy. siol;305(1):H124–34. doi: 10.1152/ajpheart.00108.2013.

Source: PubMed

赞助者和合作者

医疗条件

药物干预

3
订阅