The online version of this article (doi:10.1186/1475-2840-11-89) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
GVDM carried out the mice breeding, treatments, biochemical analysis, PV-loop experiments and infarct size determination, data and statistical analysis, and drafted the manuscript. IN, AV and WO contributed to mice breeding, treatments and biochemical analysis. WF participated in the design of the study and general supervision. PH designed the study, obtained funding, did supervision of the analysis and interpretation of data, and revised the manuscript for important intellectual content. All authors read and approved the final manuscript.
The number of patients with diabetes or the metabolic syndrome reaches epidemic proportions. On top of their diabetic cardiomyopathy, these patients experience frequent and severe cardiac ischemia-reperfusion (IR) insults, which further aggravate their degree of heart failure. Food restriction and angiotensin-converting enzyme inhibition (ACE-I) are standard therapies in these patients but the effects on cardiac IR injury have never been investigated. In this study, we tested the hypothesis that 1° food restriction and 2° ACE-I reduce infarct size and preserve cardiac contractility after IR injury in mouse models of diabetes and the metabolic syndrome.
C57Bl6/J wild type (WT) mice, leptin deficient ob/ob (model for type II diabetes) and double knock-out (LDLR-/-;ob/ob, further called DKO) mice with combined leptin and LDL-receptor deficiency (model for metabolic syndrome) were used. The effects of 12 weeks food restriction or ACE-I on infarct size and load-independent left ventricular contractility after 30 min regional cardiac ischemia were investigated. Differences between groups were analyzed for statistical significance by Student’s t-test or factorial ANOVA followed by a Fisher’s LSD post hoc test.
Infarct size was larger in ob/ob and DKO versus WT. Twelve weeks of ACE-I improved pre-ischemic left ventricular contractility in ob/ob and DKO. Twelve weeks of food restriction, with a weight reduction of 35-40%, or ACE-I did not reduce the effect of IR.
ACE-I and food restriction do not correct the increased sensitivity for cardiac IR-injury in mouse models of type II diabetes and the metabolic syndrome.
Marfella R, Di Filippo C, Esposito K, Nappo F, Piegari E, Cuzzocrea S, Berrino L, Rossi F, Giugliano D, D'Amico M: Absence of inducible nitric oxide synthase reduces myocardial damage during ischemia reperfusion in streptozotocin-induced hyperglycemic mice. Diabetes. 2004, 53: 454-462. 10.2337/diabetes.53.2.454. CrossRefPubMed
Van den Bergh A, Vanderper A, Vangheluwe P, Desjardins F, Nevelsteen I, Verreth W, Wuytack F, Holvoet P, Flameng W, Balligand JL, Herijgers P: Dyslipidemia in type II diabetic mice does not aggravate contractile impairment but increases ventricular stiffness. Cardiovasc Res. 2008, 77: 371-379. CrossRefPubMed
Buse JB, Ginsberg HN, Bakris GL, Clark NG, Costa F, Eckel R, Fonseca V, Gerstein HC, Grundy S, Nesto RW, Pignone MP, Plutzky J, Porte D, Redberg R, Stitzel KF, Stone NJ, American Heart Association American Diabetes Association, American Heart Association American Diabetes Association: Primary prevention of cardiovascular disease in people with diabetes mellitus. A Scientific statement from the American Heart Association and the American Diabetes Association. Circulation. 2007, 115: 114-126. CrossRefPubMed
Verreth W, De Keyzer D, Pelat M, Verhamme P, Ganame J, Bielicki JK, Mertens A, Quarck R, Benhabiles N, Marguerie G, Mackness B, Mackness M, Ninio E, Herregods MC, Balligand JL, Holvoet P: Weight-loss-associated induction of peroxisome proliferator-activated receptor-alpha and peroxisome proliferator-activated receptor-gamma correlate with reduced atherosclerosis and improved cardiovascular function in obese insulin-resistant mice. Circulation. 2004, 110: 3259-3269. 10.1161/01.CIR.0000147614.85888.7A. CrossRefPubMed
Crandall DL, Goldstein BM, Gabel RA, Cervoni P: Hemodynamic effects of weight reduction in the obese rat. Am J Physiol. 1984, 247: R266-R271. PubMed
ACE Inhibitor Myocardial Infarction Collaborative Group: Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. Circulation. 1998, 97: 2202-2212. CrossRef
Yang X-P, Liu Y-H, Shesely EG, Bulagannawar M, Liu F, Carretero OA: Endothelial nitric oxide gene knock-out mice: cardiac phenotypes and the effect of angiotensin-converting enzyme inhibitor on myocardial ischemia/reperfusion injury. Hypertension. 1999, 34: 24-30. 10.1161/01.HYP.34.1.24. CrossRefPubMed
Nozawa Y, Miura T, Tsuchida A, Kita H, Fukuma T, Shimamoto K: Chronic treatment with an ACE inhibitor, temocapril, lowers the threshold for the infarct size-limiting effect of ischemic preconditioning. Cardiovac Drugs Ther. 1999, 13: 151-157. 10.1023/A:1007744428819. CrossRef
Itoh S, Ding B, Shishido T, Lerner-Marmarosh N, Wang N, Maekawa N, Berk BC, Takeishi Y, Yan C, Blaxall BC, Abe J: Role of p90 ribosomal S6 kinase-mediated prorenin-converting enzyme in ischemic and diabetic myocardium. Circulation. 2006, 113: 1787-1798. 10.1161/CIRCULATIONAHA.105.578278. CrossRefPubMed
Van der Mieren G, Van den Bergh A, Nevelsteen I, Vanderper A, Flameng W, Herijgers P: Hypoxic preconditioning preserves cardiac contractility and reduces infarct size in vivo. The Open Surgery Journal. 2008, 2: 24-29. 10.2174/1874300500802010024. CrossRef
Marfella R, Esposito K, Nappo F, Siniscalchi M, Sasso FC, Portoghese M, Di Marino MP, Baldi A, Cuzzocrea S, Di Filippo C, Barboso G, Baldi F, Rossi F, D'Amico M, Giugliano D: Expression of angiogenic factors during acute coronary syndromes in human type 2 diabetes. Diabetes. 2004, 53: 2383-2391. 10.2337/diabetes.53.9.2383. CrossRefPubMed
Talukder MA, Kalyanasundaram A, Zuo L, Velayutham M, Nishijima Y, Periasamy M, Zweier JL: Is reduced SERCA2a expression detrimental or beneficial to postischemic cardiac function and injury? Evidence from heterozygous SERCA2a knockout mice. Am J Physiol Heart Circ Physiol. 2008, 294: H1426-H1434. CrossRefPubMed
Van den Bergh A, Vangheluwe P, Vanderper A, Carmeliet P, Wuytack F, Janssens S, Flameng W, Holvoet P, Herijgers P: Food-restriction in obese dyslipidaemic diabetic mice partially restores basal contractility but not contractile reserve. Eur J Heart Fail. 2009, 11: 1118-1125. 10.1093/eurjhf/hfp156. CrossRefPubMed
Mitchell JR, Verweij M, Brand K, van de Ven M, Goemaere N, van den Engel S, Chu T, Forrer F, Müller C, de Jong M, van IJcken W, IJzermans JN, Hoeijmakers JH, de Bruin RW: Short-term dietaryrestriction and fasting precondition against ischemia reperfusion injury in mice. Aging Cell. 2010, 9: 40-53. 10.1111/j.1474-9726.2009.00532.x. PubMedCentralCrossRefPubMed
Takeishi Y, Bhagwat A, Ball NA, Kirkpatrick DL, Periasamy M, Walsh RA: Effect of angiotensin-converting enzyme inhibition on protein kinase C and SR proteins in heart failure. Am J Physiol Heart Circ Physiol. 1999, 276: H53-H62.
Gross ML, Heiss N, Weckbach M, Hansen A, El-Shakmak A, Szabo A, Münter K, Ritz E, Amann K: ACE-inhibition is superior to endothelin A receptor blockade in preventing abnormal capillary supply and fibrosis of the heart in experimental diabetes. Diabetologia. 2004, 47: 316-324. 10.1007/s00125-003-1309-z. CrossRefPubMed
- Angiotensin-converting enzyme inhibition and food restriction in diabetic mice do not correct the increased sensitivity for ischemia-reperfusion injury
Gerry Van der Mieren
- BioMed Central
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