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01.09.2007 | Article

Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

verfasst von: S. Van Linthout, A. Riad, N. Dhayat, F. Spillmann, J. Du, S. Dhayat, D. Westermann, D. Hilfiker-Kleiner, M. Noutsias, U. Laufs, H.-P. Schultheiss, C. Tschöpe

Erschienen in: Diabetologia | Ausgabe 9/2007

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Abstract

Aims/hypothesis

Emerging evidence suggests that statins exert beneficial effects beyond those predicted by their cholesterol-lowering actions. We investigated whether atorvastatin influences the development of left ventricular (LV) dysfunction, independently of cholesterol-lowering, in an experimental model of type 1 diabetes mellitus cardiomyopathy.

Methods

Streptozotocin-induced diabetic rats were treated with atorvastatin (50 mg/kg daily, orally) or with vehicle for 6 weeks. LV function was analysed using tip-catheter measurements. Cardiac stainings of TNF-α, IL-1β, intercellular adhesion molecule-1, vascular cellular adhesion molecule-1, CD11a/lymphocyte-associated antigen-1, CD11b/macrophage antigen alpha, CD18/β2-integrin, ED1/CD68, collagen I and III, and Sirius Red were assessed by digital image analysis. Ras-related C3 botulinum toxin substrate (RAC1) and ras homologue gene family, member A (RHOA) activities were determined by RAC1 glutathione-S-transferase–p21-activated kinase and rhotekin pull-down assays, respectively. Cardiac lipid peroxides were measured by a colorimetric assay. The phosphorylation state of p38 mitogen-activated protein kinase (MAPK) and endothelial nitric oxide synthase (eNOS) protein production were analysed by western blot.

Results

Diabetes was associated with induced cardiac stainings of TNF-α, IL-1β, cellular adhesion molecules, increased leucocyte infiltration, macrophage residence and cardiac collagen content. In contrast, atorvastatin reduced both intramyocardial inflammation and myocardial fibrosis, resulting in improved LV function. This effect was paralleled with a normalisation of diabetes-induced RAC1 and RHOA activity, in the absence of LDL-cholesterol lowering. In addition, atorvastatin decreased diabetes-induced cardiac lipid peroxide levels and p38 MAPK phosphorylation by 1.3-fold (p < 0.05) and 3.2-fold (p < 0.0005), respectively, and normalised the reduced eNOS production caused by diabetes.

Conclusions/interpretation

These data indicate that atorvastatin, independently of its LDL-cholesterol-lowering capacity, reduces intramyocardial inflammation and myocardial fibrosis, resulting in improved LV function in an experimental model of diabetic cardiomyopathy.

Kannel WB, Hjortland M, Castelli WP (1974) Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 34:29–34PubMedCrossRef

Zarich SW, Nesto RW (1989) Diabetic cardiomyopathy. Am Heart J 118:1000–1012PubMedCrossRef

Tschope C, Walther T, Escher F et al (2005) Transgenic activation of the kallikrein-kinin system inhibits intramyocardial inflammation, endothelial dysfunction and oxidative stress in experimental diabetic cardiomyopathy. FASEB J 19:2057–2059PubMed

Asbun J, Villarreal FJ (2006) The pathogenesis of myocardial fibrosis in the setting of diabetic cardiomyopathy. J Am Coll Cardiol 47:693–700PubMedCrossRef

Lamarche B, Lemieux I, Despres JP (1999) The small, dense LDL phenotype and the risk of coronary heart disease: epidemiology, patho-physiology and therapeutic aspects. Diabetes Metab 25:199–211PubMed

King GL, Wakasaki H (1999) Theoretical mechanisms by which hyperglycemia and insulin resistance could cause cardiovascular diseases in diabetes. Diabetes Care 22(Suppl 3):C31–C37PubMed

Maytin M, Leopold J, Loscalzo J (1999) Oxidant stress in the vasculature. Curr Atheroscler Rep 1:156–164PubMed

Holvoet P, Collen D (1994) Oxidized lipoproteins in atherosclerosis and thrombosis. FASEB J 8:1279–1284PubMed

Sacks FM, Pfeffer MA, Moye LA et al (1996) The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 335:1001–1009PubMedCrossRef

10.

Takemoto M, Liao JK (2001) Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol 21:1712–1719PubMed

11.

Goldstein JL, Brown MS (1990) Regulation of the mevalonate pathway. Nature 343:425–430PubMedCrossRef

12.

Wolfrum S, Dendorfer A, Rikitake Y et al (2004) Inhibition of Rho-kinase leads to rapid activation of phosphatidylinositol 3-kinase/protein kinase Akt and cardiovascular protection. Arterioscler Thromb Vasc Biol 24:1842–1847PubMedCrossRef

13.

Mita S, Kobayashi N, Yoshida K, Nakano S, Matsuoka H (2005) Cardioprotective mechanisms of Rho-kinase inhibition associated with eNOS and oxidative stress-LOX-1 pathway in Dahl salt-sensitive hypertensive rats. J Hypertens 23:87–96PubMedCrossRef

14.

Lee TM, Lin MS, Chou TF, Tsai CH, Chang NC (2005) Effect of pravastatin on development of left ventricular hypertrophy in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 289:H220–H227PubMedCrossRef

15.

Hayashidani S, Tsutsui H, Shiomi T et al (2002) Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation 105:868–873PubMedCrossRef

16.

Tschope C, Reinecke A, Seidl U et al (1999) Functional, biochemical, and molecular investigations of renal kallikrein-kinin system in diabetic rats. Am J Physiol 277:H2333–H2340PubMed

17.

Tschope C, Heringer-Walther S, Koch M et al (2000) Myocardial bradykinin B2-receptor expression at different time points after induction of myocardial infarction. J Hypertens 18:223–238PubMedCrossRef

18.

Pauschinger M, Knopf D, Petschauer S et al (1999) Dilated cardiomyopathy is associated with significant changes in collagen type I/III ratio. Circulation 99:2750–2756PubMed

19.

Tschope C, Walther T, Koniger J et al (2004) Prevention of cardiac fibrosis and left ventricular dysfunction in diabetic cardiomyopathy in rats by transgenic expression of the human tissue kallikrein gene. FASEB J 18:828–835PubMedCrossRef

20.

Sander EE, van Delft S, ten Klooster JP et al (1998) Matrix-dependent Tiam1/Rac signaling in epithelial cells promotes either cell–cell adhesion or cell migration and is regulated by phosphatidylinositol 3-kinase. J Cell Biol 143:1385–1398PubMedCrossRef

21.

Reid T, Furuyashiki T, Ishizaki T et al (1996) Rhotekin, a new putative target for Rho bearing homology to a serine/threonine kinase, PKN, and rhophilin in the rho-binding domain. J Biol Chem 271:13556–13560PubMedCrossRef

22.

Spinale FG (2002) Matrix metalloproteinases: regulation and dysregulation in the failing heart. Circ Res 90:520–530PubMedCrossRef

23.

Wassmann S, Laufs U, Baumer AT et al (2001) Inhibition of geranylgeranylation reduces angiotensin II-mediated free radical production in vascular smooth muscle cells: involvement of angiotensin AT1 receptor expression and Rac1 GTPase. Mol Pharmacol 59:646–654PubMed

24.

Bar-On H, Roheim PS, Eder HA (1976) Serum lipoproteins and apolipoproteins in rats with streptozotocin-induced diabetes. J Clin Invest 57:714–721PubMed

25.

Bar-On H, Eisenberg S (1978) The metabolic fate of high density lipoprotein (HDL) in the diabetic rat. Diabetologia 14:65–69PubMedCrossRef

26.

Young NL, Lopez DR, McNamara DJ (1988) Contributions of absorbed dietary cholesterol and cholesterol synthesized in small intestine to hypercholesterolemia in diabetic rats. Diabetes 37: 1151–1156PubMedCrossRef

27.

Schaefer JR, Schweer H, Ikewaki K et al (1999) Metabolic basis of high density lipoproteins and apolipoprotein A-I increase by HMG-CoA reductase inhibition in healthy subjects and a patient with coronary artery disease. Atherosclerosis 144:177–184PubMedCrossRef

28.

Rawson RB (2003) The SREBP pathway—insights from Insigs and insects. Nat Rev Mol Cell Biol 4:631–640PubMedCrossRef

29.

Wassmann S, Laufs U, Baumer AT et al (2001) HMG-CoA reductase inhibitors improve endothelial dysfunction in normocholesterolemic hypertension via reduced production of reactive oxygen species. Hypertension 37:1450–1457PubMed

30.

Mahfouz MM, Kummerow FA (2005) Atorvastatin reduces the plasma lipids and oxidative stress but did not reverse the inhibition of prostacyclin generation by aortas in streptozotocin diabetic rats. Prostaglandins Other Lipid Mediat 76:59–73PubMed

31.

Tomlinson KC, Gardiner SM, Hebden RA, Bennett T (1992) Functional consequences of streptozotocin-induced diabetes mellitus, with particular reference to the cardiovascular system. Pharmacol Rev 44:103–150PubMed

32.

Schaible TF, Malhotra A, Bauman WA, Scheuer J (1983) Left ventricular function after chronic insulin treatment in diabetic and normal rats. J Mol Cell Cardiol 15:445–458PubMedCrossRef

33.

Litwin SE, Raya TE, Anderson PG, Daugherty S, Goldman S (1990) Abnormal cardiac function in the streptozotocin-diabetic rat. Changes in active and passive properties of the left ventricle. J Clin Invest 86:481–488PubMedCrossRef

34.

Koch M, Wendorf M, Dendorfer A et al (2003) Cardiac kinin level in experimental diabetes mellitus: role of kininases. Am J Physiol Heart Circ Physiol 285:H418–H423PubMed

35.

Bidasee KR, Zhang Y, Shao CH et al (2004) Diabetes increases formation of advanced glycation end products on Sarco(endo)plasmic reticulum Ca²⁺-ATPase. Diabetes 53:463–473PubMedCrossRef

36.

Vasanji Z, Dhalla NS, Netticadan T (2004) Increased inhibition of SERCA2 by phospholamban in the type I diabetic heart. Mol Cell Biochem 261:245–249PubMedCrossRef

37.

Montanari D, Yin H, Dobrzynski E et al (2005) Kallikrein gene delivery improves serum glucose and lipid profiles and cardiac function in streptozotocin-induced diabetic rats. Diabetes 54:1573–1580PubMedCrossRef

38.

Lefer AM, Campbell B, Shin YK, Scalia R, Hayward R, Lefer DJ (1999) Simvastatin preserves the ischemic-reperfused myocardium in normocholesterolemic rat hearts. Circulation 100:178–184PubMed

39.

Modrak J (1980) Collagen metabolism in the myocardium from streptozotocin-diabetic rats. Diabetes 29:547–550PubMedCrossRef

40.

Yoshida M, Sawada T, Ishii H et al (2001) Hmg-CoA reductase inhibitor modulates monocyte-endothelial cell interaction under physiological flow conditions in vitro: involvement of Rho GTPase-dependent mechanism. Arterioscler Thromb Vasc Biol 21:1165–1171PubMed

41.

Khayat ZA, Tong P, Yaworsky K, Bloch RJ, Klip A (2000) Insulin-induced actin filament remodeling colocalizes actin with phosphatidylinositol 3-kinase and GLUT4 in L6 myotubes. J Cell Sci 113(Pt 2):279–290PubMed

42.

Wojciak-Stothard B, Williams L, Ridley AJ (1999) Monocyte adhesion and spreading on human endothelial cells is dependent on Rho-regulated receptor clustering. J Cell Biol 145:1293–1307PubMedCrossRef

43.

Uhlik MT, Abell AN, Johnson NL et al (2003) Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock. Nat Cell Biol 5:1104–1110PubMedCrossRef

44.

Westermann D, Rutschow S, Van Linthout S et al (2006) 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 49:2507–2513PubMedCrossRef

45.

Omi H, Okayama N, Shimizu M et al (2003) Statins inhibit high glucose-mediated neutrophil-endothelial cell adhesion through decreasing surface expression of endothelial adhesion molecules by stimulating production of endothelial nitric oxide. Microvasc Res 65:118–124PubMedCrossRef

Titel: Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy
verfasst von: S. Van Linthout
A. Riad
N. Dhayat
F. Spillmann
J. Du
S. Dhayat
D. Westermann
D. Hilfiker-Kleiner
M. Noutsias
U. Laufs
H.-P. Schultheiss
C. Tschöpe
Publikationsdatum: 01.09.2007
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 9/2007
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-007-0719-8

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