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Diabetologia

Erschienen in:

01.06.2006 | Article

Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca²⁺-ATPase and myosin heavy chain isozyme switch

verfasst von: S.-Y. Li, X. Yang, A. F. Ceylan-Isik, M. Du, N. Sreejayan, J. Ren

Erschienen in: Diabetologia | Ausgabe 6/2006

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Abstract

Aims/hypothesis

Obesity is an independent risk factor for heart diseases but the underlying mechanism is not clear. This study examined cardiac contraction, oxidative stress, oxidative modification of sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA) and the myosin heavy chain (MHC) isoform switch in obese mice.

Methods

Mechanical properties were evaluated in ventricular myocytes from C57BL/6J lean and Lep/Lep obese mice (formerly known as ob/ob mice), including peak shortening (PS), time to 50 or 90% PS, time to 50 or 90% relengthening (TR₅₀, TR₉₀), maximal velocity of shortening/relengthening (±dL/dt), intracellular Ca²⁺ and its decay (τ). Oxidative stress, lipid peroxidation, protein damage and SERCA activity were assessed by glutathione/glutathione disulfide, malondialdehyde, protein carbonyl and ⁴⁵Ca²⁺ uptake, respectively. NADPH oxidase was determined by immunoblotting.

Results

Myocytes from Lep/Lep mice displayed depressed PS and ± dL/dt, prolonged TR₅₀, TR₉₀, elevated resting [Ca²⁺]_i, prolonged τ, reduced contractile capacity at high stimulus frequencies and diminished responsiveness to extracellular Ca²⁺ compared with lean controls. Cardiac glutathione/glutathione disulfide was decreased whereas malondialdehyde, protein carbonyl, membrane p47^phox and membrane gp91^phox were increased in the Lep/Lep group. SERCA isoenzyme 2a was markedly modified by oxidation in Lep/Lep hearts and associated with decreased ⁴⁵Ca²⁺ uptake. The MHC isozyme displayed a shift from the α to the β isoform in Lep/Lep hearts. Short-term incubation of angiotensin II with myocytes mimicked the mechanical defects, SERCA oxidation and ⁴⁵Ca²⁺ uptake seen in Lep/Lep myocytes. Incubation of the NADPH oxidase inhibitor apocynin with Lep/Lep myocytes alleviated contractile defects without reversing SERCA oxidation or activity.

Conclusions/interpretation

These data indicate that obesity-related cardiac defects may be related to NADPH oxidase activation, oxidative damage to SERCA and the MHC isozyme switch.

Eckel RH, Barouch WW, Ershow AG (2002) Report of the National Heart, Lung, and Blood Institute-National Institute of Diabetes and Digestive and Kidney Diseases Working Group on the pathophysiology of obesity-associated cardiovascular disease. Circulation 105:2923–2928PubMedCrossRef

Ren J, Sowers JR, Walsh MF, Brown RA (2000) Reduced contractile response to insulin and IGF-I in ventricular myocytes from genetically obese Zucker rats. Am J Physiol Heart Circ Physiol 279:H1708–1714PubMed

Montague CT, Farooqi IS, Whitehead JP, et al (1997) Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387:903–908PubMedCrossRef

Ren J (2004) Leptin and hyperleptinemia—from friend to foe for cardiovascular function. J Endocrinol 181:1–10PubMedCrossRef

Barouch LA, Cappola TP, Harrison RW, et al (2003) Combined loss of neuronal and endothelial nitric oxide synthase causes premature mortality and age-related hypertrophic cardiac remodeling in mice. J Mol Cell Cardiol 35:637–644PubMedCrossRef

Nickola MW, Wold LE, Colligan PB, Wang GJ, Samson WK, Ren J (2000) Leptin attenuates cardiac contraction in rat ventricular myocytes. Role of NO. Hypertension 36:501–505PubMed

Wold LE, Relling DP, Duan J, Norby FL, Ren J (2002) Abrogated leptin-induced cardiac contractile response in ventricular myocytes under spontaneous hypertension: role of Jak/STAT pathway. Hypertension 39:69–74PubMedCrossRef

Xu FP, Chen MS, Wang YZ, et al (2004) Leptin induces hypertrophy via endothelin-1-reactive oxygen species pathway in cultured neonatal rat cardiomyocytes. Circulation 110:1269–1275PubMedCrossRef

Minhas KM, Khan SA, Raju SVY, et al (2005) Leptin repletion restores depressed {beta}-adrenergic contractility in ob/ob mice independently of cardiac hypertrophy. J Physiol 565:463–474PubMedCrossRef

10.

Ren J (2005) Lessons from the leptin paradox in cardiac regulation—too much versus too little. J Physiol 565:347PubMedCrossRef

11.

Correia ML, Haynes WG (2004) Leptin, obesity and cardiovascular disease. Curr Opin Nephrol Hypertens 13:215–223PubMedCrossRef

12.

Uzun H, Zengin K, Taskin M, Aydin S, Simsek G, Dariyerli N (2004) Changes in leptin, plasminogen activator factor and oxidative stress in morbidly obese patients following open and laparoscopic Swedish adjustable gastric banding. Obes Surg 14:659–665PubMedCrossRef

13.

McClung JP, Roneker CA, Mu W, et al (2004) Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase. Proc Natl Acad Sci USA 101:8852–8857PubMedCrossRef

14.

Furukawa S, Fujita T, Shimabukuro M, et al (2004) Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114:1752–1761PubMed

15.

Katakam PV, Tulbert CD, Snipes JA, Erdos B, Miller AW, Busija DW (2005) Impaired insulin-induced vasodilation in small coronary arteries of Zucker obese rats is mediated by reactive oxygen species. Am J Physiol Heart Circ Physiol 288:H854–860PubMedCrossRef

16.

Boudina S, Sena S, O’Neill BT, Tathireddy P, Young ME, Abel ED (2005) Reduced mitochondrial oxidative capacity and increased mitochondrial uncoupling impair myocardial energetics in obesity. Circulation 112:2686–2695PubMedCrossRef

17.

Razeghi P, Young ME, Cockrill TC, Frazier OH, Taegtmeyer H (2002) Downregulation of myocardial myocyte enhancer factor 2C and myocyte enhancer factor 2C-regulated gene expression in diabetic patients with nonischemic heart failure. Circulation 106:407–411PubMedCrossRef

18.

Russell LK, Finck BN, Kelly DP (2005) Mouse models of mitochondrial dysfunction and heart failure. J Mol Cell Cardiol 38:81–91PubMedCrossRef

19.

Tankersley CG, O’Donnell C, Daood MJ, et al (1998) Leptin attenuates respiratory complications associated with the obese phenotype. J Appl Physiol 85:2261–2269PubMed

20.

O’Donnell CP, Tankersley CG, Polotsky VP, Schwartz AR, Smith PL (2000) Leptin, obesity, and respiratory function. Respir Physiol 119:63–70CrossRef

21.

Yang X, Palanichamy K, Ontko AC, et al (2005) Newly synthetic chromium complex—chromium (phenylalanine)₃ improves insulin responsiveness and reduces whole body glucose tolerance. FEBS Lett 579:1458–1464PubMedCrossRef

22.

Li SY, Du M, Dolence EK, et al (2005) Aging induces cardiac diastolic dysfunction, oxidative stress, accumulation of advanced glycation endproducts and protein modification. Aging Cell 4:57–64PubMedCrossRef

23.

Husain K (2004) Physical conditioning modulates rat cardiac vascular endothelial growth factor gene expression in nitric oxide-deficient hypertension. Biochem Biophys Res Commun 320:1169–1174PubMedCrossRef

24.

Blough ER, Rennie ER, Zhang F, Reiser PJ (1996) Enhanced electrophoretic separation and resolution of myosin heavy chain in mammalian and avian skeletal muscles. Anal Biochem 233:31–35PubMedCrossRef

25.

Reiser PJ, Kline WO (1998) Electrophoretic separation and quantitation of cardiac myosin heavy chain isoforms in eight mammalian species. Am J Physiol Heart Circ Physiol 274:H1048–H1053

26.

Yan LJ, Orr WC, Sohal RS (1998) Identification of oxidized proteins based on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, immunochemical detection, isoelectric focusing, and microsequencing. Anal Biochem 263:67–71PubMedCrossRef

27.

Adachi T, Weisbrod RM, Pimentel DR, et al (2004) S-Glutathiolation by peroxynitrite activates SERCA during arterial relaxation by nitric oxide. Nat Med 10:1200–1207PubMedCrossRef

28.

Rundell VL, Manaves V, Martin AF, de Tombe PP (2005) Impact of beta-myosin heavy chain isoform expression on cross-bridge cycling kinetics. Am J Physiol Heart Circ Physiol 287:H408–H413CrossRef

29.

Olsson MC, Palmer BM, Stauffer BL, Leinwand LA, Moore RL (2004) Morphological and functional alterations in ventricular myocytes from male transgenic mice with hypertrophic cardiomyopathy. Circ Res 94:201–207PubMedCrossRef

30.

Krenz M, Robbins J (2004) Impact of beta-myosin heavy chain expression on cardiac function during stress. J Am Coll Cardiol 44:2390–2397PubMedCrossRef

31.

Lowes BD, Gilbert EM, Abraham WT, et al (2002) Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents. N Engl J Med 346:1357–1365PubMedCrossRef

32.

Cai H, Griendling KK, Harrison DG (2003) The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol Sci 24:471–478PubMedCrossRef

33.

Touyz RM, Chen X, Tabet F, et al (2002) Expression of a functionally active gp91phox-containing neutrophil-type NAD(P)H oxidase in smooth muscle cells from human resistance arteries: regulation by angiotensin II. Circ Res 90:1205–1213PubMedCrossRef

34.

Privratsky JR, Wold LE, Sowers JR, Quinn MT, Ren J (2003) AT1 blockade prevents glucose-induced cardiac dysfunction in ventricular myocytes: role of the AT1 receptor and NADPH oxidase. Hypertension 42:206–212PubMedCrossRef

35.

Dalle-Donne I, Scaloni A, Giustarini D, et al (2005) Proteins as biomarkers of oxidative/nitrosative stress in diseases: the contribution of redox proteomics. Mass Spectrom Rev 24:55–99PubMedCrossRef

36.

Squier TC (2001) Oxidative stress and protein aggregation during biological aging. Exp Gerontol 36:1539–1550PubMedCrossRef

37.

Pantke U, Volk T, Schmutzler M, Kox WJ, Sitte N, Grune T (1999) Oxidized proteins as a marker of oxidative stress during coronary heart surgery. Free Radic Biol Med 27:1080–1086PubMedCrossRef

38.

Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM (1994) Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432PubMedCrossRef

39.

Schwartz MW, Porte D Jr (2005) Diabetes, obesity, and the brain. Science 307:375–379PubMedCrossRef

40.

Mazumder PK, O’Neill BT, Roberts MW, et al (2004) Impaired cardiac efficiency and increased fatty acid oxidation in insulin-resistant ob/ob mouse hearts. Diabetes 53:2366–2374PubMedCrossRef

41.

Dong F, Zhang X, Yang X, et al (2006) Impaired cardiac contractile function in ventricular myocytes from leptin deficient ob/ob obese mice. J Endocrinol 188:25–36PubMedCrossRef

42.

Sabbah HN (2004) Effects of cardiac support device on reverse remodeling: molecular, biochemical, and structural mechanisms. J Card Fail 10:S207–S214PubMedCrossRef

43.

Kass DA, Bronzwaer JG, Paulus WJ (2004) What mechanisms underlie diastolic dysfunction in heart failure? Circ Res 94:1533–1542PubMedCrossRef

44.

Belke DD, Swanson EA, Dillmann WH (2004) Decreased sarcoplasmic reticulum activity and contractility in diabetic db/db mouse heart. Diabetes 53:3201–3208PubMedCrossRef

45.

Pierce GN, Russell JC (1997) Regulation of intracellular Ca²⁺ in the heart during diabetes. Cardiovasc Res 34:41–47PubMedCrossRef

46.

Li JM, Shah AM (2002) Intracellular localization and preassembly of the NADPH oxidase complex in cultured endothelial cells. J Biol Chem 277:19952–19960PubMedCrossRef

47.

Stolk J, Hiltermann TJ, Dijkman JH, Verhoeven AJ (1994) Characteristics of the inhibition of NADPH oxidase activation in neutrophils by apocynin, a methoxy-substituted catechol. Am J Respir Cell Mol Biol 11:95–102PubMed

48.

Goldhaber JI, Qayyum MS (2000) Oxygen free radicals and excitation-contraction coupling. Antioxid Redox Signal 2:55–64PubMedCrossRef

49.

Zhong Y, Reiser PJ, Matlib MA (2003) Gender differences in myosin heavy chain-beta and phosphorylated phospholamban in diabetic rat hearts. Am J Physiol Heart Circ Physiol 285:H2688–H2693PubMed

50.

Carnes CA, Geisbuhler TP, Reiser PJ (2004) Age-dependent changes in contraction and regional myocardial myosin heavy chain isoform expression in rats. J Appl Physiol 97:446–453PubMedCrossRef

Titel: Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca2+-ATPase and myosin heavy chain isozyme switch
verfasst von: S.-Y. Li
X. Yang
A. F. Ceylan-Isik
M. Du
N. Sreejayan
J. Ren
Publikationsdatum: 01.06.2006
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 6/2006
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-006-0229-0

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Cardiac contractile dysfunction in Lep/Lep obesity is accompanied by NADPH oxidase activation, oxidative modification of sarco(endo)plasmic reticulum Ca²⁺-ATPase and myosin heavy chain isozyme switch

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