Effect of obesity reduction on preservation of heart function and attenuation of left ventricular remodeling, oxidative stress and inflammation in obese mice

Journal of Translational Medicine

Hon-Kan Yip³  Chia-Hung Yen¹  Sarah Chua⁴  Sheng-Ying Chung⁴  Han-Tan Chai⁴  Yen-Yi Zhen³  Steve Leu³  Ching-Yen Tsai⁵  Hsueh-Wen Chang²  Yung-Lung Chen⁴  Tzu-Hsien Tsai⁴  Chu-Feng Liu⁶  Hui-Ting Wang⁶ 

[1] Department of Biological Science and Technology, National Pingtung University of Science and Technology, Pingtung, Taiwan;Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan;Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan;Division of cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan;Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan;Department of Emergency Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan

关键词: Fibrosis;    Apoptosis;    Oxidative stress;    Inflammation;    Obesity;   

Others  :  1205936
DOI  :  10.1186/1479-5876-10-145

 received in 2012-03-22, accepted in 2012-07-02,  发布年份 2012

【 摘 要 】

Background

Obesity is an important cardiovascular risk factor. This study tested the effect of obesity reduction on preserving left ventricular ejection fraction (LVEF) and attenuating inflammation, oxidative stress and LV remodeling in obese mice.

Methods and results

Eight-week-old C57BL/6 J mice (n=24) were equally divided into control (fed a control diet for 22 weeks), obesity (high-fat diet, 22 weeks), and obese reduction (OR) (high-fat diet, 14 weeks; then control diet, 8 weeks). Animals were sacrificed at post 22-week high-fat diet and the LV myocardium collected. Heart weight, body weight, abdominal-fat weight, total cholesterol level and fasting blood glucose were higher in obesity than in control and OR (all p<0.001). Inflammation measured by mRNA expressions of IL-6, MMP-9, PAI-1 and leptin and protein expression of NF-κB was higher, whereas anti-inflammation measured by mRNA expressions of adiponectin and INF-γ was lower in obesity than in control and OR (all p<0.003). Oxidative protein expressions of NOX-1, NOX-2 and oxidized protein were higher, whereas expression of anti-oxidant markers HO-1 and NQO-1 were lower (all p<0.01); and apoptosis measured by Bax and caspase 3 was higher, whereas anti-apoptotic Bcl-2 was lower in obesity as compared with control and OR (all p<0.001). The expressions of fibrotic markers phosphorylated Smad3 and TGF-β were higher, whereas expression of anti-fibrotic phosphorylated Smad1/5 and BMP-2 were lower (all p<0.02); and LVEF was lower, whereas the LV remodeling was higher in obesity than in control and OR (all p<0.001).

Conclusion

Impaired LVEF, enhanced LV remodeling, inflammation, fibrosis, oxidative stress and apoptosis were reversed by reduction in mouse obesity.

【 授权许可】

   
2012 Wang et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

【 参考文献 】

• [1]Hassanzadeh J, Mohammadbeigi A, Eshrati B, Moemenbellah-Fard MD: Estimation of the regional burden of non-communicable diseases due to obesity and overweight in Markazi province, Iran, 2006–2007. J Cardiovasc Dis Res 2012, 3:26-31.
• [2]Das SR, Alexander KP, Chen AY, Powell-Wiley TM, Diercks DB, Peterson ED, Roe MT, de Lemos JA: Impact of body weight and extreme obesity on the presentation, treatment, and in-hospital outcomes of 50,149 patients with ST-Segment elevation myocardial infarction results from the NCDR (National Cardiovascular Data Registry). J Am Coll Cardiol 2011, 58:2642-2650.
• [3]Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM: Prevalence of overweight and obesity in the United States, 1999–2004. JAMA 2006, 295:1549-1555.
• [4]Lee ES, Kim YH, Beck SH, Lee S, Oh SW: Depressive mood and abdominal fat distribution in overweight premenopausal women. Obes Res 2005, 13:320-325.
• [5]Samper-Ternent R, Al Snih S: Obesity in Older Adults: Epidemiology and Implications for Disability and Disease. Rev Clin Gerontol 2012, 22:10-34.
• [6]Lin WY, Lee LT, Chen CY, Lo H, Hsia HH, Liu IL, Lin RS, Shau WY, Huang KC: Optimal cut-off values for obesity: using simple anthropometric indices to predict cardiovascular risk factors in Taiwan. Int J Obes Relat Metab Disord 2002, 26:1232-1238.
• [7]Jee SH, Pastor-Barriuso R, Appel LJ, Suh I, Miller ER, Guallar E: Body mass index and incident ischemic heart disease in South Korean men and women. Am J Epidemiol 2005, 162:42-48.
• [8]Oh SW, Shin SA, Yun YH, Yoo T, Huh BY: Cut-off point of BMI and obesity-related comorbidities and mortality in middle-aged Koreans. Obes Res 2004, 12:2031-2040.
• [9]Song YM, Sung J, Davey Smith G, Ebrahim S: Body mass index and ischemic and hemorrhagic stroke: a prospective study in Korean men. Stroke 2004, 35:831-836.
• [10]Oh SW, Yoon YS, Shin SA: Effects of excess weight on cancer incidences depending on cancer sites and histologic findings among men: Korea National Health Insurance Corporation Study. J Clin Oncol 2005, 23:4742-4754.
• [11]Oh SW: Obesity and metabolic syndrome in Korea. Diabetes Metab J 2011, 35:561-566.
• [12]Li R, Lu W, Jia J, Zhang S, Shi L, Li Y, Yang Q, Kan H: Relationships between indices of obesity and its cardiovascular comorbidities in a Chinese population. Circ J 2008, 72:973-978.
• [13]Mikirova NA, Casciari JJ, Hunninghake RE, Beezley MM: Effect of weight reduction on cardiovascular risk factors and CD34-positive cells in circulation. Int J Med Sci 2011, 8:445-452.
• [14]Bondia-Pons I: Ryan L. Martinez JA: Oxidative stress and inflammation interactions in human obesity. J Physiol Biochem; 2012.
• [15]Balistreri CR, Caruso C, Candore G: The role of adipose tissue and adipokines in obesity-related inflammatory diseases. Mediators Inflamm 2010, 2010:802078.
• [16]Roos CJ, Quax PH, Jukema JW: Cardiovascular metabolic syndrome: mediators involved in the pathophysiology from obesity to coronary heart disease. Biomark Med 2012, 6:35-52.
• [17]Cosentino F, Eto M, De Paolis P, van der Loo B, Bachschmid M, Ullrich V, Kouroedov A, Delli Gatti C, Joch H, Volpe M, Luscher TF: High glucose causes upregulation of cyclooxygenase-2 and alters prostanoid profile in human endothelial cells: role of protein kinase C and reactive oxygen species. Circulation 2003, 107:1017-1023.
• [18]Hulsmans M: Van Dooren E. Holvoet P: Mitochondrial Reactive Oxygen Species and Risk of Atherosclerosis. Curr Atheroscler Rep; 2012.
• [19]Hulsmans M, Holvoet P: The vicious circle between oxidative stress and inflammation in atherosclerosis. J Cell Mol Med 2010, 14:70-78.
• [20]Sun CK, Chang LT, Sheu JJ, Chiang CH, Lee FY, Wu CJ, Chua S, Fu M, Yip HK: Bone marrow-derived mononuclear cell therapy alleviates left ventricular remodeling and improves heart function in rat-dilated cardiomyopathy. Crit Care Med 2009, 37:1197-1205.
• [21]Gong HP, Tan HW, Fang NN, Song T, Li SH, Zhong M, Zhang W, Zhang Y: Impaired left ventricular systolic and diastolic function in patients with metabolic syndrome as assessed by strain and strain rate imaging. Diabetes Res Clin Pract 2009, 83:300-307.
• [22]Turkbey EB, McClelland RL, Kronmal RA, Burke GL, Bild DE, Tracy RP, Arai AE, Lima JA, Bluemke DA: The impact of obesity on the left ventricle: the Multi-Ethnic Study of Atherosclerosis (MESA). JACC Cardiovasc Imaging 2010, 3:266-274.
• [23]Charakida M, Finer N: Drug treatment of obesity in cardiovascular disease. Am J Cardiovasc Drugs 2012, 12:93-104.
• [24]Lakhani M, Fein S: Effects of obesity and subsequent weight reduction on left ventricular function. Cardiol Rev 2011, 19:1-4.
• [25]Gallagher R, Kirkness A, Armari E, Davidson PM: Weight management issues and strategies for people with high cardiovascular risk undertaking an Australian weight loss program: A focus group study. Nurs Health Sci 2012, 14:18-24.
• [26]Van Heek M, Compton DS, France CF, Tedesco RP, Fawzi AB, Graziano MP, Sybertz EJ, Strader CD, Davis HR: Diet-induced obese mice develop peripheral, but not central, resistance to leptin. J Clin Invest 1997, 99:385-390.
• [27]Sung PH, Sun CK, Ko SF, Chang LT, Sheu JJ, Lee FY, Wu CJ, Chua S, Yip HK: Impact of hyperglycemic control on left ventricular myocardium. A molecular and cellular basic study in a diabetic rat model. Int Heart J 2009, 50:191-206.
• [28]Fang ZY, Prins JB, Marwick TH: Diabetic cardiomyopathy: evidence, mechanisms, and therapeutic implications. Endocr Rev 2004, 25:543-567.
• [29]Poornima IG, Parikh P, Shannon RP: Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res 2006, 98:596-605.
• [30]Weissberg PL, Bennett MR: Atherosclerosis–an inflammatory disease. N Engl J Med 1999, 340:1928-1929.
• [31]Frangogiannis NG, Smith CW, Entman ML: The inflammatory response in myocardial infarction. Cardiovasc Res 2002, 53:31-47.
• [32]Yip HK, Wu CJ, Chang HW, Yang CH, Yeh KH, Chua S, Fu M: Levels and values of serum high-sensitivity C-reactive protein within 6 hours after the onset of acute myocardial infarction. Chest 2004, 126:1417-1422.
• [33]van der Wal AC, Becker AE, van der Loos CM, Das PK: Site of intimal rupture or erosion of thrombosed coronary atherosclerotic plaques is characterized by an inflammatory process irrespective of the dominant plaque morphology. Circulation 1994, 89:36-44.
• [34]Bikman BT: A role for sphingolipids in the pathophysiology of obesity-induced inflammation. Cell Mol Life Sci 2012.
• [35]Sheu JJ, Chua S, Sun CK, Chang LT, Yen CH, Wu CJ, Fu M, Yip HK: Intra-coronary administration of cyclosporine limits infarct size, attenuates remodeling and preserves left ventricular function in porcine acute anterior infarction. Int J Cardiol 2011, 147:79-87.
• [36]Chen YT, Sun CK, Lin YC, Chang LT, Chen YL, Tsai TH, Chung SY, Chua S, Kao YH, Yen CH, Shao PL, Chang KC, Leu S, Yip HK: Adipose-derived mesenchymal stem cell protects kidneys against ischemia-reperfusion injury through suppressing oxidative stress and inflammatory reaction. J Transl Med 2011, 9:51. BioMed Central Full Text
• [37]Sun CK, Yen CH, Lin YC, Tsai TH, Chang LT, Kao YH, Chua S, Fu M, Ko SF, Leu S, Yip HK: Autologous transplantation of adipose-derived mesenchymal stem cells markedly reduced acute ischemia-reperfusion lung injury in a rodent model. J Transl Med 2011, 9:118. BioMed Central Full Text
• [38]Vogt B, Bochud M, Burnier M: The association of aldosterone with obesity-related hypertension and the metabolic syndrome. Semin Nephrol 2007, 27:529-537.