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01.06.2008 | ORIGINAL CONTRIBUTION

Reduced MMP-2 activity contributes to cardiac fibrosis in experimental diabetic cardiomyopathy

verfasst von: Sophie Van Linthout, Ute Seeland, Alexander Riad, Oleg Eckhardt, Mathias Hohl, Nasser Dhayat, Utz Richter, Jens W. Fischer, Michael Böhm, Matthias Pauschinger, Heinz-Peter Schultheiss, Carsten Tschöpe, MD

Erschienen in: Basic Research in Cardiology | Ausgabe 4/2008

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Abstract

Objective

To evaluate the regulation of matrix metalloproteinase (MMP)-2 in diabetic cardiomyopathy.

Methods

Left ventricle (LV) function was determined by a micro-tip catheter in streptozotocin (STZ)-induced diabetic rats, 2 or 6 weeks (w) after STZ-application. LV total collagen, collagen type I and III content were immunohistologically analyzed and quantified by digital image analysis. LV collagen type I, III and MMP-2 mRNA expression was quantified by real-time RT-PCR. LV pro- and active MMP-2 levels were analyzed by zymography; Smad 7, membrane type (MT)1-MMP and tissue inhibitor metalloproteinase (TIMP)-2 protein levels by Western Blot.

Results

STZ-induced diabetes was associated with a time-dependent impairment of LV diastolic and systolic function. This was paralleled by a time-dependent increase in LV total collagen content, despite reduced LV collagen type I and III mRNA levels, indicating a role of post-transcriptional/post-translational changes of extracellular matrix regulation. Six weeks (w) after STZ-injection, MMP-2 mRNA expression and pro-MMP-2 levels were 2.7-fold (P < 0.005) and 1.3-fold (P < 0.05) reduced versus controls, respectively, whereas active MMP-2 was decreased to undetectable levels 6 w post-STZ. Concomitantly, Smad 7 and TIMP-2 protein levels were 1.3-fold (P < 0.05) and 10-fold (P < 0.005) increased in diabetics versus controls, respectively, whereas the 45 kDa form of MT1-MMP was undetectable in diabetics.

Conclusion

Under STZ-diabetic conditions, cardiac fibrosis is associated with a dysregulation in extracellular matrix degradation. This condition is featured by reduced MMP-2 activity, concomitant with increased Smad 7 and TIMP-2 and decreased MT1-MMP protein expression, which differs from mechanisms involved in dilated and ischemic heart disease.

Ahmed SH, Clark LL, Pennington WR, Webb CS, Bonnema DD, Leonardi AH, McClure CD, Spinale FG, Zile MR (2006) Matrix metalloproteinases/tissue inhibitors of metalloproteinases: relationship between changes in proteolytic determinants of matrix composition and structural, functional, and clinical manifestations of hypertensive heart disease. Circulation 113:2089–2096PubMedCrossRef

Aimes RT, Quigley JP (1995) Matrix metalloproteinase-2 is an interstitial collagenase. Inhibitor-free enzyme catalyzes the cleavage of collagen fibrils and soluble native type I collagen generating the specific 3/4- and 1/4-length fragments. J Biol Chem 270:5872–5876PubMedCrossRef

Akula A, Kota MK, Gopisetty SG, Chitrapu RV, Kalagara M, Kalagara S, Veeravalli KK, Gomedhikam JP (2003) Biochemical, histological and echocardiographic changes during experimental cardiomyopathy in STZ-induced diabetic rats. Pharmacol Res 48:429–435PubMedCrossRef

Asbun J, Manso AM, Villarreal FJ (2005) Profibrotic influence of high glucose concentration on cardiac fibroblast functions: effects of losartan and vitamin E. Am J Physiol Heart Circ Physiol 288:H227–H234PubMedCrossRef

Bell DS (1995) Diabetic cardiomyopathy. A unique entity or a complication of coronary artery disease? Diabetes Care 18:708–714PubMedCrossRef

Berman M, Teerlink J, Li L, Mahimkar R, Zhu BQ, Nguyen A, Dahi S, Karliner J, Lovett DH (2006) Cardiac matrix metalloproteinase-2 expression independently induces marked ventricular remodeling and systolic dysfunction. Am J Physiol Heart Circ Physiol 292:H1847–H1860CrossRef

Bidasee KR, Zhang Y, Shao CH, Wang M, Patel KP, Dincer UD, Besch HR Jr. (2004) Diabetes increases formation of advanced glycation end products on Sarco(endo)plasmic reticulum Ca2+-ATPase. Diabetes 53:463–473PubMedCrossRef

Bollano E, Omerovic E, Svensson H, Waagstein F, Fu M (2006) Cardiac remodeling rather than disturbed myocardial energy metabolism is associated with cardiac dysfunction in diabetic rats. Int J Cardiol [Epub ahead of print]

Butler GS, Butler MJ, Atkinson SJ, Will H, Tamura T, Schade van Westrum S, Crabbe T, Clements J, d’Ortho MP, Murphy G (1998) The TIMP2 membrane type 1 metalloproteinase “receptor” regulates the concentration and efficient activation of progelatinase A. A kinetic study. J Biol Chem 273:871–880PubMedCrossRef

10.

Coker ML, Zellner JL, Crumbley AJ, Spinale FG (1999) Defects in matrix metalloproteinase inhibitory stoichiometry and selective MMP induction in patients with nonischemic or ischemic dilated cardiomyopathy. Ann N Y Acad Sci 878:559–562PubMedCrossRef

11.

Dollery CM, McEwan JR, Henney AM (1995) Matrix metalloproteinases and cardiovascular disease. Circ Res 77:863–868PubMed

12.

Han SY, Jee YH, Han KH, Kang YS, Kim HK, Han JY, Kim YS, Cha DR (2006) An imbalance between matrix metalloproteinase-2 and tissue inhibitor of matrix metalloproteinase-2 contributes to the development of early diabetic nephropathy. Nephrol Dial Transplant 21:2406–2416PubMedCrossRef

13.

Hayashi T, Sohmiya K, Ukimura A, Endoh S, Mori T, Shimomura H, Okabe M, Terasaki F, Kitaura Y (2003) Angiotensin II receptor blockade prevents microangiopathy and preserves diastolic function in the diabetic rat heart. Heart 89:1236–1242PubMedCrossRef

14.

Kuzuya M, Asai T, Kanda S, Maeda K, Cheng XW, Iguchi A (2001) Glycation cross-links inhibit matrix metalloproteinase-2 activation in vascular smooth muscle cells cultured on collagen lattice. Diabetologia 44:433–436PubMedCrossRef

15.

Kuzuya M, Nakamura K, Sasaki T, Cheng XW, Itohara S, Iguchi A (2006) Effect of MMP-2 deficiency on atherosclerotic lesion formation in apoE-deficient mice. Arterioscler Thromb Vasc Biol 26:1120–1125PubMedCrossRef

16.

Lee EO, Kang JL, Chong YH (2005) The amyloid-beta peptide suppresses transforming growth factor-beta1-induced matrix metalloproteinase-2 production via Smad7 expression in human monocytic THP-1 cells. J Biol Chem 280:7845–7853PubMedCrossRef

17.

Lupia E, Elliot SJ, Lenz O, Zheng F, Hattori M, Striker GE, Striker LJ (1999) IGF-1 decreases collagen degradation in diabetic NOD mesangial cells: implications for diabetic nephropathy. Diabetes 48:1638–1644PubMedCrossRef

18.

Massague J (2000) How cells read TGF-beta signals. Nat Rev Mol Cell Biol 1:169–178PubMedCrossRef

19.

Matsusaka H, Ide T, Matsushima S, Ikeuchi M, Kubota T, Sunagawa K, Kinugawa S, Tsutsui H (2006) Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload. Hypertension 47:711–717PubMedCrossRef

20.

Ohuchi E, Imai K, Fujii Y, Sato H, Seiki M, Okada Y (1997) Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. J Biol Chem 272:2446–2451PubMedCrossRef

21.

Pauschinger M, Knopf D, Petschauer S, Doerner A, Poller W, Schwimmbeck PL, Kuhl U, Schultheiss HP (1999) Dilated cardiomyopathy is associated with significant changes in collagen type I/III ratio. Circulation 99:2750–2756PubMed

22.

Phanish MK, Wahab NA, Colville-Nash P, Hendry BM, Dockrell ME (2006) The differential role of Smad2 and Smad3 in the regulation of pro-fibrotic TGFbeta1 responses in human proximal-tubule epithelial cells. Biochem J 393:601–607PubMedCrossRef

23.

Pulaski L, Landstrom M, Heldin CH, Souchelnytskyi S (2001) Phosphorylation of Smad7 at Ser-249 does not interfere with its inhibitory role in transforming growth factor-beta-dependent signaling but affects Smad7-dependent transcriptional activation. J Biol Chem 276:14344–14349PubMed

24.

Rittie L, Berton A, Monboisse JC, Hornebeck W, Gillery P (1999) Decreased contraction of glycated collagen lattices coincides with impaired matrix metalloproteinase production. Biochem Biophys Res Commun 264:488–492PubMedCrossRef

25.

Riva E, Andreoni G, Bianchi R, Latini R, Luvara G, Jeremic G, Traquandi C, Tuccinardi L (1998) Changes in diastolic function and collagen content in normotensive and hypertensive rats with long-term streptozotocin-induced diabetes. Pharmacol Res 37:233–240PubMedCrossRef

26.

Rutschow S, Li J, Schultheiss HP, Pauschinger M (2006) Myocardial proteases and matrix remodeling in inflammatory heart disease. Cardiovasc Res 69:646–656PubMedCrossRef

27.

Sato H, Takino T, Okada Y, Cao J, Shinagawa A, Yamamoto E, Seiki M (1994) A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 370:61–65PubMedCrossRef

28.

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

29.

Seeland U, Kouchi I, Zolk O, Itter G, Linz W, Bohm M (2002) Effect of ramipril and furosemide treatment on interstitial remodeling in post-infarction heart failure rat hearts. J Mol Cell Cardiol 34:151–163PubMedCrossRef

30.

Seeland U, Selejan S, Engelhardt S, Muller P, Lohse MJ, Bohm M (2007) Interstitial remodeling in beta1-adrenergic receptor transgenic mice. Basic Res Cardiol 102:183–193PubMedCrossRef

31.

Shehadeh A, Regan TJ (1995) Cardiac consequences of diabetes mellitus. Clin Cardiol 18:301–305PubMedCrossRef

32.

Singh R, Song RH, Alavi N, Pegoraro AA, Singh AK, Leehey DJ (2001) High glucose decreases matrix metalloproteinase-2 activity in rat mesangial cells via transforming growth factor-beta1. Exp Nephrol 9:249–257PubMedCrossRef

33.

Stanton H, Gavrilovic J, Atkinson SJ, d’Ortho MP, Yamada KM, Zardi L, Murphy G (1998) The activation of ProMMP-2 (gelatinase A) by HT1080 fibrosarcoma cells is promoted by culture on a fibronectin substrate and is concomitant with an increase in processing of MT1-MMP (MMP-14) to a 45 kDa form. J Cell Sci 111(Pt 18):2789–2798PubMed

34.

Stilli D, Lagrasta C, Berni R, Bocchi L, Savi M, Delucchi F, Graiani G, Monica M, Maestri R, Baruffi S, Rossi S, Macchi E, Musso E, Quaini F (2007) Preservation of ventricular performance at early stages of diabetic cardiomyopathy involves changes in myocyte size, number and intercellular coupling. Basic Res Cardiol 102:488–499PubMedCrossRef

35.

Tack I, Elliot SJ, Potier M, Rivera A, Striker GE, Striker LJ (2002) Autocrine activation of the IGF-I signaling pathway in mesangial cells isolated from diabetic NOD mice. Diabetes 51:182–188PubMedCrossRef

36.

Thomas CV, Coker ML, Zellner JL, Handy JR, Crumbley AJ 3rd, Spinale FG (1998) Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Circulation 97:1708–1715PubMed

37.

Tschope C, Spillmann F, Rehfeld U, Koch M, Westermann D, Altmann C, Dendorfer A, Walther T, Bader M, Paul M, Schultheiss HP, Vetter R (2004) Improvement of defective sarcoplasmic reticulum Ca2+ transport in diabetic heart of transgenic rats expressing the human kallikrein-1 gene. Faseb J 18:1967–1969PubMedCrossRef

38.

Tschope C, Walther T, Escher F, Spillmann F, Du J, Altmann C, Schimke I, Bader M, Sanchez-Ferrer CF, Schultheiss HP, Noutsias M (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

39.

Tschope C, Walther T, Koniger J, Spillmann F, Westermann D, Escher F, Pauschinger M, Pesquero JB, Bader M, Schultheiss HP, Noutsias M (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

40.

Vinik AI, Ziegler D (2007) Diabetic cardiovascular autonomic neuropathy. Circulation 115:387–397PubMedCrossRef

41.

Wang B, Hao J, Jones SC, Yee MS, Roth JC, Dixon IM (2002) Decreased Smad 7 expression contributes to cardiac fibrosis in the infarcted rat heart. Am J Physiol Heart Circ Physiol 282:H1685–H1696PubMed

42.

Wang B, Omar A, Angelovska T, Drobic V, Rattan SG, Jones SC, Dixon IM (2007) Regulation of collagen synthesis by inhibitory Smad7 in cardiac myofibroblasts. Am J Physiol Heart Circ Physiol 293:H1282–H1290PubMedCrossRef

43.

Westermann D, Rutschow S, Jager S, Linderer A, Anker S, Riad A, Unger T, Schultheiss HP, Pauschinger M, Tschope C (2007) Contributions of inflammation and cardiac matrix metalloproteinase activity to cardiac failure in diabetic cardiomyopathy: the role of angiotensin type 1 receptor antagonism. Diabetes 56:641–646PubMedCrossRef

44.

Westermann D, Van Linthout S, Dhayat S, Dhayat N, Schmidt A, Noutsias M, Song XY, Spillmann F, Riad A, Schultheiss HP, Tschope C (2007) Tumor necrosis factor-alpha antagonism protects from myocardial inflammation and fibrosis in experimental diabetic cardiomyopathy. Basic Res Cardiol 102:500–507PubMedCrossRef

45.

Wrana JL (2000) Regulation of Smad activity. Cell 100:189–192PubMedCrossRef

Titel: Reduced MMP-2 activity contributes to cardiac fibrosis in experimental diabetic cardiomyopathy
verfasst von: Sophie Van Linthout
Ute Seeland
Alexander Riad
Oleg Eckhardt
Mathias Hohl
Nasser Dhayat
Utz Richter
Jens W. Fischer
Michael Böhm
Matthias Pauschinger
Heinz-Peter Schultheiss
Carsten Tschöpe, MD
Publikationsdatum: 01.06.2008
Verlag: D. Steinkopff-Verlag
Erschienen in: Basic Research in Cardiology / Ausgabe 4/2008
Print ISSN: 0300-8428
Elektronische ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-008-0715-2

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Abstract

Objective

Methods

Results

Conclusion

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