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DOI: 10.1055/s-0034-1387761
Increased Gene Expression of the Cardiac Endothelin System in Obese Mice
Publication History
received 17 June 2014
accepted 05 August 2014
Publication Date:
02 September 2014 (online)
Abstract
Obesity is a well-known risk factor of atherosclerosis and heart failure. In the human heart, a local endothelin system containing prepro-endothelin-1, endothelin-converting enzyme-1, and endothelin receptors A and B has been described. The endothelin system is activated in heart failure; however, the impact of obesity on the cardiac endothelin system is unknown. In this study, 18-week-old male C57BL/6 mice fed either a control diet or a high-fat diet for 10 weeks were analyzed. High-fat diet significantly increased the body weight of the animals and augmented low-density lipoprotein, high-density lipoprotein, and cholesterol plasma levels, compared to control. The animal groups showed no significant differences in left ventricular size or function (heart rate, ejection fraction, fractional shortening, left ventricular posterior wall thickness, cardiac output) after control or high-fat diet. We did not observe signs of cardiac hypertrophy or changes in markers of cardiac fibrosis in these heart samples. The cardiac expression of prepro-endothelin-1 mRNA, endothelin-converting enzyme-1 mRNA, and protein and endothelin receptors A and B mRNA was increased in 18-week-old obese C57BL/6 mice compared to animals with normal weight (p<0.05 vs. control). Furthermore, endothelin-1 plasma levels showed an increasing trend. In conclusion, an increased expression of genes of the endothelin system was observed in the hearts of 18-week-old mice after high-fat diet, possibly contributing to later cardiovascular complications of obesity.
* Both first authors contributed equally to this study.
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References
- 1 Lamounier-Zepter V, Bornstein SR, Ehrhart-Bornstein M. Mechanisms of obesity-related hypertension. Horm Metab Res 2004; 36: 376-380
- 2 Masaki T. Historical review: Endothelin. Trends Pharmacol Sci 2004; 25: 219-224
- 3 Sakai S, Miyauchi T, Kobayashi M, Yamaguchi I, Goto K, Sugishita Y. Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Nature 1996; 384: 353-355
- 4 Jeng AY. Utility of endothelin-converting enzyme inhibitors for the treatment of cardiovascular diseases. Curr Opin Invest Drugs 2003; 4: 1076-1081
- 5 Wunderlich C, Schober K, Kasper M, Heerwagen C, Marquetant R, Ebner B, Forkmann M, Schoen S, Braun-Dullaeus RC, Schmeisser A, Strasser RH. Nitric oxide synthases are crucially involved in the development of the severe cardiomyopathy of caveolin-1 knockout mice. Biochem Biophys Res Commun 2008; 377: 769-774
- 6 Whittaker P, Kloner RA, Boughner DR, Pickering JG. Quantitative assessment of myocardial collagen with picrosirius red staining and circularly polarized light. Basic Res Cardiol 1994; 89: 397-410
- 7 Desmarchelier C, Dahlhoff C, Keller S, Sailer M, Jahreis G, Daniel H. C57Bl/6 N mice on a western diet display reduced intestinal and hepatic cholesterol levels despite a plasma hypercholesterolemia. BMC Genomics 2012; 13: 84
- 8 Escola-Gil JC, Llaverias G, Julve J, Jauhiainen M, Mendez-Gonzalez J, Blanco-Vaca F. The cholesterol content of Western diets plays a major role in the paradoxical increase in high-density lipoprotein cholesterol and upregulates the macrophage reverse cholesterol transport pathway. Arterioscler Thromb Vasc Biol 2011; 31: 2493-2499
- 9 Kim S, Sohn I, Ahn JI, Lee KH, Lee YS, Lee YS. Hepatic gene expression profiles in a long-term high-fat diet-induced obesity mouse model. Gene 2004; 340: 99-109
- 10 Kotseva K, Stagmo M, De Bacquer D, De Backer G, Wood D. Group EIS. Treatment potential for cholesterol management in patients with coronary heart disease in 15 European countries: findings from the EUROASPIRE II survey. Atherosclerosis 2008; 197: 710-717
- 11 Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr 2003; 77: 1146-1155
- 12 Freeman HC, Hugill A, Dear NT, Ashcroft FM, Cox RD. Deletion of nicotinamide nucleotide transhydrogenase: a new quantitive trait locus accounting for glucose intolerance in C57BL/6J mice. Diabetes 2006; 55: 2153-2156
- 13 Ayala JE, Samuel VT, Morton GJ, Obici S, Croniger CM, Shulman GI, Wasserman DH, McGuinness OP, Consortium NIHMMPC. Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice. Dis Model Mech 2010; 3: 525-534
- 14 Rottman JN, Ni G, Brown M. Echocardiographic evaluation of ventricular function in mice. Echocardiography 2007; 24: 83-89
- 15 Stypmann J. Doppler ultrasound in mice. Echocardiography 2007; 24: 97-112
- 16 de Haas HJ, Arbustini E, Fuster V, Kramer CM, Narula J. Molecular imaging of the cardiac extracellular matrix. Circ Res 2014; 114: 903-915
- 17 Barton M, Carmona R, Morawietz H, d’Uscio LV, Goettsch W, Hillen H, Haudenschild CC, Krieger JE, Munter K, Lattmann T, Luscher TF, Shaw S. Obesity is associated with tissue-specific activation of renal angiotensin-converting enzyme in vivo: evidence for a regulatory role of endothelin. Hypertension 2000; 35: 329-336
- 18 Traupe T, D’Uscio LV, Muenter K, Morawietz H, Vetter W, Barton M. Effects of obesity on endothelium-dependent reactivity during acute nitric oxide synthase inhibition: modulatory role of endothelin. Clin Sci (Lond) 2002; 103 (Suppl. 01) 13S-15S
- 19 Adiarto S, Emoto N, Iwasa N, Yokoyama M. Obesity-induced upregulation of myocardial endothelin-1 expression is mediated by leptin. Biochem Biophys Res Commun 2007; 353: 623-627
- 20 Tousoulis D, Charakida M, Stefanadis C. Inflammation and endothelial dysfunction as therapeutic targets in patients with heart failure. Int J Cardiol 2005; 100: 347-353
- 21 Parrinello G, Scaglione R, Pinto A, Corrao S, Cecala M, Di Silvestre G, Amato P, Licata A, Licata G. Central obesity and hypertension: the role of plasma endothelin. Am J Hypertens 1996; 9: 1186-1191
- 22 Morawietz H, Goettsch W, Szibor M, Barton M, Shaw S, Hakim K, Zerkowski HR, Holtz J. Angiotensin-converting enzyme inhibitor therapy prevents upregulation of endothelin-converting enzyme-1 in failing human myocardium. Biochem Biophys Res Commun 2002; 295: 1057-1061
- 23 Ellinghaus P, Scheubel RJ, Dobrev D, Ravens U, Holtz J, Huetter J, Nielsch U, Morawietz H. Comparing the global mRNA expression profile of human atrial and ventricular myocardium with high-density oligonucleotide arrays. J Thorac Cardiovasc Surg 2005; 129: 1383-1390
- 24 Morawietz H, Szibor M, Goettsch W, Bartling B, Barton M, Shaw S, Koerfer R, Zerkowski HR, Holtz J. Deloading of the left ventricle by ventricular assist device normalizes increased expression of endothelin ETA receptors but not endothelin-converting enzyme-1 in patients with end-stage heart failure. Circulation. 2000 102. III188-III193
- 25 Sedmera D, Harris BS, Grant E, Zhang N, Jourdan J, Kurkova D, Gourdie RG. Cardiac expression patterns of endothelin-converting enzyme (ECE): implications for conduction system development. Dev Dyn 2008; 237: 1746-1753
- 26 Vignon-Zellweger N, Rahnenfuhrer J, Theuring F, Hocher B. Analysis of cardiac and renal endothelin receptors by in situ hybridization in mice. Clin Lab 2012; 58: 939-949
- 27 Fareh J, Touyz RM, Schiffrin EL, Thibault G. Endothelin-1 and angiotensin II receptors in cells from rat hypertrophied heart. Receptor regulation and intracellular Ca2 + modulation. Circ Res 1996; 78: 302-311
- 28 Niemann B, Rohrbach S, Catar RA, Muller G, Barton M, Morawietz H. Native and oxidized low-density lipoproteins stimulate endothelin-converting enzyme-1 expression in human endothelial cells. Biochem Biophys Res Commun 2005; 334: 747-753
- 29 Muller G, Catar RA, Niemann B, Barton M, Knels L, Wendel M, Morawietz H. Upregulation of endothelin receptor B in human endothelial cells by low-density lipoproteins. Exp Biol Med (Maywood) 2006; 231: 766-771
- 30 Morawietz H, Bornstein SR. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med 2014; 371: 181