Assessment of cardiac inflammation and remodeling during the development of streptozotocin-induced diabetic cardiomyopathy in vivo: A time course analysis

Becher,P. M.; Lindner,D.; Fröhlich,M.; Savvatis,K.; Westermann,D.; Tschöpe,C.

doi:10.3892/ijmm.2013.1368

Assessment of cardiac inflammation and remodeling during the development of streptozotocin-induced diabetic cardiomyopathy in vivo: A time course analysis

Authors:
- P. M. Becher
- D. Lindner
- M. Fröhlich
- K. Savvatis
- D. Westermann
- C. Tschöpe
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Affiliations: Department of Cardiology and Pneumology, Charité University Hospital Berlin, Campus Benjamin Franklin, D-12200 Berlin, Germany, Berlin-Brandenburg Center for Regenerative Therapies, Charité University Hospital Berlin, Campus Virchow, D-13353 Berlin, Germany, German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Charité, D-13347 Berlin, Germany
Published online on: May 2, 2013 https://doi.org/10.3892/ijmm.2013.1368
Pages: 158-164

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Abstract

In this study, we examined cardiac inflammation, fibrosis and left ventricular (LV) function during the development of streptozotocin (STZ)-induced diabetic cardiomyopathy using an animal model of diabetes mellitus (DM). Diabetes was induced in 22 Sprague‑Dawley rats by an intraperitoneal single injection of STZ (70 mg/kg). Non-diabetic animals served as the controls (n=6). LV function was documented using the conductance catheter technique 2 and 6 weeks after the induction of diabetes. Cardiac tissue was analyzed for cardiac immune cell infiltration, oxidative stress and remodeling in rats with STZ-induced diabetes at 2 different time points by immunohistochemistry. Cardiac function was significantly impaired in the diabetic animals. After 2 weeks, the induction of diabetes resulted in impaired cardiac function indexed by a decrease in systolic and diastolic LV function. This impairment of LV performance continued for up to 6 weeks after the STZ injection. This was associated with an increase in cardiac CD3+ and CD8a+ immune cell invasion and fibrosis, indexed by an increase in collagen content (p<0.05). Furthermore, oxidative stress response and matrix remodeling were increased after 2 weeks and this continued for up to 6 weeks after the induction of diabetes. In conclusion, cardiac dysfunction is associated with cardiac inflammation and adverse remodeling in experimental diabetic cardiomyopathy. Our results suggest that the model of STZ-induced diabetic cardiomyopathy is a robust model for investigating cardiac immune response and LV remodeling processes under diabetic conditions.

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1.	Poornima IG, Parikh P and Shannon RP: Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ Res. 98:596–605. 2006. View Article : Google Scholar : PubMed/NCBI
2.	Grundy SM, Benjamin IJ, Burke GL, et al: Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation. 100:1134–1146. 1999. View Article : Google Scholar : PubMed/NCBI
3.	Howard BV and Wylie-Rosett J: Sugar and cardiovascular disease: a statement for healthcare professionals from the Committee on Nutrition of the Council on Nutrition, Physical Activity, and Metabolism of the American Heart Association. Circulation. 106:523–527. 2002. View Article : Google Scholar
4.	Devereux RB, Roman MJ, Paranicas M, et al: Impact of diabetes on cardiac structure and function: the strong heart study. Circulation. 101:2271–2276. 2000. View Article : Google Scholar : PubMed/NCBI
5.	Cai L, Li W, Wang G, Guo L, Jiang Y and Kang YJ: Hyperglycemia-induced apoptosis in mouse myocardium: mitochondrial cytochrome C-mediated caspase-3 activation pathway. Diabetes. 51:1938–1948. 2002. View Article : Google Scholar : PubMed/NCBI
6.	Heymans S, Hirsch E, Anker SD, et al: Inflammation as a therapeutic target in heart failure? a scientific statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail. 11:119–129. 2009. View Article : Google Scholar
7.	Tschope C, Walther T, Koniger J, et al: Prevention of cardiac fibrosis and left ventricular dysfunction in diabetic cardiomyopathy in rats by transgenic expression of the human tissue kallikrein gene. FASEB J. 18:828–835. 2004. View Article : Google Scholar : PubMed/NCBI
8.	Tschope C, Spillmann F, Rehfeld U, et al: Improvement of defective sarcoplasmic reticulum Ca2⁺ transport in diabetic heart of transgenic rats expressing the human kallikrein-1 gene. FASEB J. 18:1967–1969. 2004.PubMed/NCBI
9.	Westermann D, Rutschow S, Jager S, et al: Contributions of inflammation and cardiac matrix metalloproteinase activity to cardiac failure in diabetic cardiomyopathy: the role of angiotensin type 1 receptor antagonism. Diabetes. 56:641–646. 2007. View Article : Google Scholar
10.	Riad A, Westermann D, Van Linthout S, et al: Enhancement of endothelial nitric oxide synthase production reverses vascular dysfunction and inflammation in the hindlimbs of a rat model of diabetes. Diabetologia. 51:2325–2332. 2008. View Article : Google Scholar : PubMed/NCBI
11.	Westermann D, Van Linthout S, Dhayat S, et al: Cardioprotective and anti-inflammatory effects of interleukin converting enzyme inhibition in experimental diabetic cardiomyopathy. Diabetes. 56:1834–1841. 2007. View Article : Google Scholar
12.	Westermann D, Rutschow S, Van Linthout S, et al: Inhibition of p38 mitogen-activated protein kinase attenuates left ventricular dysfunction by mediating pro-inflammatory cardiac cytokine levels in a mouse model of diabetes mellitus. Diabetologia. 49:2507–2513. 2006. View Article : Google Scholar
13.	Westermann D, Becher PM, Lindner D, et al: Selective PDE5A inhibition with sildenafil rescues left ventricular dysfunction, inflammatory immune response and cardiac remodeling in angiotensin II-induced heart failure in vivo. Basic Res Cardiol. 107:3082012. View Article : Google Scholar : PubMed/NCBI
14.	Becher PM, Lindner D, Miteva K, et al: Role of heart rate reduction in the prevention of experimental heart failure: comparison between If-channel blockade and beta-receptor blockade. Hypertension. 59:949–957. 2012. View Article : Google Scholar : PubMed/NCBI
15.	Wang J, Song Y, Elsherif L, et al: Cardiac metallothionein induction plays the major role in the prevention of diabetic cardiomyopathy by zinc supplementation. Circulation. 113:544–554. 2006. View Article : Google Scholar : PubMed/NCBI
16.	Westermann D, Van Linthout S, Dhayat S, et al: Tumor necrosis factor-alpha antagonism protects from myocardial inflammation and fibrosis in experimental diabetic cardiomyopathy. Basic Res Cardiol. 102:500–507. 2007. View Article : Google Scholar : PubMed/NCBI
17.	Van Linthout S, Riad A, Dhayat N, et al: Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy. Diabetologia. 50:1977–1986. 2007.PubMed/NCBI
18.	Dorenkamp M, Riad A, Stiehl S, et al: Protection against oxidative stress in diabetic rats: role of angiotensin AT(1) receptor and beta 1-adrenoceptor antagonism. Eur J Pharmacol. 520:179–187. 2005. View Article : Google Scholar : PubMed/NCBI
19.	Savvatis K, Westermann D, Schultheiss HP and Tschope C: Kinins in cardiac inflammation and regeneration: insights from ischemic and diabetic cardiomyopathy. Neuropeptides. 44:119–125. 2010. View Article : Google Scholar : PubMed/NCBI
20.	Yeghiazaryan K, Bauriedel G, Schild HH and Golubnitschaja O: Prediction of degeneration of native and bioprosthetic aortic valves: issue-related particularities of diabetes mellitus. Infect Disord Drug Targets. 8:88–99. 2008. View Article : Google Scholar : PubMed/NCBI
21.	Marwick TH: Diabetic heart disease. Heart. 92:296–300. 2006.
22.	Tyagi SC and Hayden MR: Role of nitric oxide in matrix remodeling in diabetes and heart failure. Heart Fail Rev. 8:23–28. 2003. View Article : Google Scholar : PubMed/NCBI
23.	Tsioufis C, Bafakis I, Kasiakogias A and Stefanadis C: The role of matrix metalloproteinases in diabetes mellitus. Curr Top Med Chem. 2:1159–1165. 2012. View Article : Google Scholar
24.	Leask A: Potential therapeutic targets for cardiac fibrosis: TGFbeta, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation. Circ Res. 106:1675–1680. 2010. View Article : Google Scholar : PubMed/NCBI
25.	Hammoud L, Lu X, Lei M and Feng Q: Deficiency in TIMP-3 increases cardiac rupture and mortality post-myocardial infarction via EGFR signaling: beneficial effects of cetuximab. Basic Res Cardiol. 106:459–471. 2011. View Article : Google Scholar : PubMed/NCBI
26.	Bugger H and Abel ED: Mitochondria in the diabetic heart. Cardiovasc Res. 88:229–240. 2010. View Article : Google Scholar : PubMed/NCBI
27.	Henderson BC and Tyagi SC: Oxidative mechanism and homeostasis of proteinase/antiproteinase in congestive heart failure. J Mol Cell Cardiol. 41:959–962. 2006. View Article : Google Scholar : PubMed/NCBI
28.	La Rocca G, Di Stefano A, Eleuteri E, et al: Oxidative stress induces myeloperoxidase expression in endocardial endothelial cells from patients with chronic heart failure. Basic Res Cardiol. 104:307–320. 2009.PubMed/NCBI
29.	Regan TJ, Wu CF, Yeh CK, Oldewurtel HA and Haider B: Myocardial composition and function in diabetes. The effects of chronic insulin use. Circ Res. 49:1268–1277. 1981. View Article : Google Scholar : PubMed/NCBI
30.	Iribarren C, Karter AJ, Go AS, et al: Glycemic control and heart failure among adult patients with diabetes. Circulation. 103:2668–2673. 2001. View Article : Google Scholar : PubMed/NCBI
31.	Dhalla NS, Pierce GN, Innes IR and Beamish RE: Pathogenesis of cardiac dysfunction in diabetes mellitus. Can J Cardiol. 1:263–281. 1985.PubMed/NCBI