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From the Division of Cardiothoracic Surgery, Medical University of South
Carolina, Charleston.
Correspondence to Francis G. Spinale, MD, PhD, Division of Cardiothoracic Surgery, RM 418 CSB, 171 Ashley Ave, Medical University of South Carolina, Charleston, SC 29425.
Background—One of the hallmarks of
dilated cardiomyopathy (DCM) is left
ventricular (LV) remodeling. The matrix metalloproteinases
(MMPs) are a family of enzymes that contribute to extracellular
remodeling in several disease states. Additionally, a family of
inhibitors called tissue inhibitors of MMPs
(TIMPs) has been shown to exist and to tightly regulate MMP activity.
However, the types of MMPs and TIMPs expressed within the normal and
DCM LV myocardium and the relation to MMP activity
remain unexplored.
Methods and Results—Relative LV myocardial MMP activity was
determined in the normal (n=8) and idiopathic DCM (n=7) human LV
myocardium by substrate zymography. Relative LV myocardial
abundance of interstitial collagenase (MMP-1),
stromelysin (MMP-3), 72 kD gelatinase (MMP-2), 92 kD gelatinase
(MMP-9), TIMP-1, and TIMP-2 were measured with quantitative
immunoblotting. LV myocardial MMP zymographic activity
increased with DCM compared with normal (984±149 versus 413±64
pixels, P<.05). With DCM, LV myocardial abundance of
MMP-1 decreased to 16±6% (P<.05), MMP-3 increased to
563±212% (P<.05), MMP-9 increased to 422±64%
(P<.05), and MMP-2 was unchanged when compared with
normal. LV myocardial abundance of TIMP-1 and TIMP-2 increased by
>500% with DCM. A high-molecular-weight immunoreactive band for both
TIMP-1 and TIMP-2, suggesting a TIMP/MMP complex, was increased >600%
with DCM.
Conclusions—This study demonstrated increased LV myocardial
MMP activity and evidence for independent regulatory mechanisms of MMP
and TIMP expression with DCM. These findings suggest that selective
inhibition of MMP species within the LV myocardium may
provide a novel therapeutic target in patients with DCM.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Increased Matrix Metalloproteinase Activity and Selective Upregulation in LV Myocardium From Patients With End-Stage Dilated Cardiomyopathy
Key Words: cardiomyopathy • enzymes • myocardium
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G. Suzuki, H. Morita, T. Mishima, V. G. Sharov, A. Todor, E. J. Tanhehco, A. E. Rudolph, E. G. McMahon, S. Goldstein, and H. N. Sabbah Effects of Long-Term Monotherapy With Eplerenone, a Novel Aldosterone Blocker, on Progression of Left Ventricular Dysfunction and Remodeling in Dogs With Heart Failure Circulation, December 3, 2002; 106(23): 2967 - 2972. [Abstract] [Full Text] [PDF]
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M. Pauschinger, K. Chandrasekharan, J. Li, W. Poller, M. Noutsias, C. Tschope, and H.-P. Schultheiss Inflammation and extracellular matrix protein metabolism: two sides of myocardial remodelling Eur. Heart J. Suppl., December 1, 2002; 4(suppl_I): I49 - I53. [Abstract] [PDF]
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D. Li, V. Williams, L. Liu, H. Chen, T. Sawamura, T. Antakli, and J. L. Mehta LOX-1 inhibition in myocardial ischemia-reperfusion injury: modulation of MMP-1 and inflammation Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1795 - H1801. [Abstract] [Full Text] [PDF]
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J. Li, P. Lothar Schwimmbeck, C. Tschope, S. Leschka, L. Husmann, S. Rutschow, F. Reichenbach, M. Noutsias, U. Kobalz, W. Poller, et al. Collagen degradation in a murine myocarditis model: relevance of matrix metalloproteinase in association with inflammatory induction Cardiovasc Res, November 1, 2002; 56(2): 235 - 247. [Abstract] [Full Text] [PDF]
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W. Wang, C. J. Schulze, W. L. Suarez-Pinzon, J. R.B. Dyck, G. Sawicki, and R. Schulz Intracellular Action of Matrix Metalloproteinase-2 Accounts for Acute Myocardial Ischemia and Reperfusion Injury Circulation, September 17, 2002; 106(12): 1543 - 1549. [Abstract] [Full Text] [PDF]
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M. J Sierevogel, E. Velema, F. J van der Meer, M. O. Nijhuis, M. Smeets, D. P.V de Kleijn, C. Borst, and G. Pasterkamp Matrix metalloproteinase inhibition reduces adventitial thickening and collagen accumulation following balloon dilation Cardiovasc Res, September 1, 2002; 55(4): 864 - 869. [Abstract] [Full Text] [PDF]
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G. L. Brower, A. L. Chancey, S. Thanigaraj, B. B. Matsubara, and J. S. Janicki Cause and effect relationship between myocardial mast cell number and matrix metalloproteinase activity Am J Physiol Heart Circ Physiol, August 1, 2002; 283(2): H518 - H525. [Abstract] [Full Text] [PDF]
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A. K. Death, S. Nakhla, K. C. Y. McGrath, S. Martell, D. K. Yue, W. Jessup, and D. S. Celermajer Nitroglycerin upregulates matrix metalloproteinase expression by human macrophages J. Am. Coll. Cardiol., June 19, 2002; 39(12): 1943 - 1950. [Abstract] [Full Text] [PDF]
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J. D. Stroud, C. F. Baicu, M. A. Barnes, F. G. Spinale, and M. R. Zile Viscoelastic properties of pressure overload hypertrophied myocardium: effect of serine protease treatment Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2324 - H2335. [Abstract] [Full Text] [PDF]
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Y. Iwanaga, T. Aoyama, Y. Kihara, Y. Onozawa, T. Yoneda, and S. Sasayama Excessive activation of matrix metalloproteinases coincides with left ventricular remodeling during transition from hypertrophy to heart failure in hypertensive rats J. Am. Coll. Cardiol., April 17, 2002; 39(8): 1384 - 1391. [Abstract] [Full Text] [PDF]
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W. S. Bradham, G. Moe, K. A. Wendt, A. A. Scott, A. Konig, M. Romanova, G. Naik, and F. G. Spinale TNF-alpha and myocardial matrix metalloproteinases in heart failure: relationship to LV remodeling Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1288 - H1295. [Abstract] [Full Text] [PDF]
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F. G. Spinale Matrix Metalloproteinases: Regulation and Dysregulation in the Failing Heart Circ. Res., March 22, 2002; 90(5): 520 - 530. [Abstract] [Full Text] [PDF]
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P. Pacher, L. Liaudet, P. Bai, L. Virag, J. G. Mabley, G. Hasko, and C. Szabo Activation of Poly(ADP-Ribose) Polymerase Contributes to Development of Doxorubicin-Induced Heart Failure J. Pharmacol. Exp. Ther., March 1, 2002; 300(3): 862 - 867. [Abstract] [Full Text] [PDF]
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Y. Y. Li, T. Kadokami, P. Wang, C. F. McTiernan, and A. M. Feldman MMP inhibition modulates TNF-alpha transgenic mouse phenotype early in the development of heart failure Am J Physiol Heart Circ Physiol, March 1, 2002; 282(3): H983 - H989. [Abstract] [Full Text] [PDF]
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W. S. Bradham, B. Bozkurt, H. Gunasinghe, D. Mann, and F. G. Spinale Tumor necrosis factor-alpha and myocardial remodeling in progression of heart failure: a current perspective Cardiovasc Res, March 1, 2002; 53(4): 822 - 830. [Abstract] [Full Text] [PDF]
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I. Mayers, T. Hurst, L. Puttagunta, A. Radomski, T. Mycyk, G. Sawicki, D. Johnson, and M. W. Radomski Cardiac surgery increases the activity of matrix metalloproteinases and nitric oxide synthase in human hearts J. Thorac. Cardiovasc. Surg., October 1, 2001; 122(4): 746 - 752. [Abstract] [Full Text] [PDF]
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T. Walther, A. Schubert, V. Falk, C. Binner, A. Kanev, S. Bleiziffer, C. Walther, N. Doll, R. Autschbach, and F. W. Mohr Regression of Left Ventricular Hypertrophy After Surgical Therapy for Aortic Stenosis Is Associated With Changes in Extracellular Matrix Gene Expression Circulation, September 18, 2001; 104 (2009): I-54 - I-58. [Abstract] [Full Text] [PDF]
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D. L. Mann and H. Taegtmeyer Dynamic Regulation of the Extracellular Matrix After Mechanical Unloading of the Failing Human Heart: Recovering the Missing Link in Left Ventricular Remodeling Circulation, September 4, 2001; 104(10): 1089 - 1091. [Full Text] [PDF]
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Y. Y. Li, Y. Feng, C. F. McTiernan, W. Pei, C. S. Moravec, P. Wang, W. Rosenblum, R. L. Kormos, and A. M. Feldman Downregulation of Matrix Metalloproteinases and Reduction in Collagen Damage in the Failing Human Heart After Support With Left Ventricular Assist Devices Circulation, September 4, 2001; 104(10): 1147 - 1152. [Abstract] [Full Text] [PDF]
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T. Etoh, C. Joffs, A. M. Deschamps, J. Davis, K. Dowdy, J. Hendrick, S. Baicu, R. Mukherjee, M. Manhaini, and F. G. Spinale Myocardial and interstitial matrix metalloproteinase activity after acute myocardial infarction in pigs Am J Physiol Heart Circ Physiol, September 1, 2001; 281(3): H987 - H994. [Abstract] [Full Text] [PDF]
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N. Sivasubramanian, M. L. Coker, K. M. Kurrelmeyer, W. R. MacLellan, F. J. DeMayo, F. G. Spinale, and D. L. Mann Left Ventricular Remodeling in Transgenic Mice With Cardiac Restricted Overexpression of Tumor Necrosis Factor Circulation, August 14, 2001; 104(7): 826 - 831. [Abstract] [Full Text] [PDF]
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E. E.J.M. Creemers, J. P.M. Cleutjens, J. F.M. Smits, and M. J.A.P. Daemen Matrix Metalloproteinase Inhibition After Myocardial Infarction: A New Approach to Prevent Heart Failure? Circ. Res., August 3, 2001; 89(3): 201 - 210. [Abstract] [Full Text] [PDF]
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M. L. Coker, J. R. Jolly, C. Joffs, T. Etoh, J. R. Holder, B. R. Bond, and F. G. Spinale Matrix metalloproteinase expression and activity in isolated myocytes after neurohormonal stimulation Am J Physiol Heart Circ Physiol, August 1, 2001; 281(2): H543 - H551. [Abstract] [Full Text] [PDF]
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B. K. Podesser, D. A. Siwik, F. R. Eberli, F. Sam, S. Ngoy, J. Lambert, K. Ngo, C. S. Apstein, and W. S. Colucci ETA-receptor blockade prevents matrix metalloproteinase activation late postmyocardial infarction in the rat Am J Physiol Heart Circ Physiol, March 1, 2001; 280(3): H984 - H991. [Abstract] [Full Text] [PDF]
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D. A. Siwik, P. J. Pagano, and W. S. Colucci Oxidative stress regulates collagen synthesis and matrix metalloproteinase activity in cardiac fibroblasts Am J Physiol Cell Physiol, January 1, 2001; 280(1): C53 - C60. [Abstract] [Full Text] [PDF]
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 Y. Y. Li, Y. Q. Feng, T. Kadokami, C. F. McTiernan, R. Draviam, S. C. Watkins, and A. M. Feldman Myocardial extracellular matrix remodeling in transgenic mice overexpressing tumor necrosis factor alpha can be modulated by anti-tumor necrosis factor alpha therapy PNAS, November 7, 2000; 97(23): 12746 - 12751. [Abstract] [Full Text] [PDF]
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F. G. Spinale, M. L. Coker, L. J. Heung, B. R. Bond, H. R. Gunasinghe, T. Etoh, A. T. Goldberg, J. L. Zellner, and A. J. Crumbley A Matrix Metalloproteinase Induction/Activation System Exists in the Human Left Ventricular Myocardium and Is Upregulated in Heart Failure Circulation, October 17, 2000; 102(16): 1944 - 1949. [Abstract] [Full Text] [PDF]
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S. Kinugawa, H. Tsutsui, S. Hayashidani, T. Ide, N. Suematsu, S. Satoh, H. Utsumi, and A. Takeshita Treatment With Dimethylthiourea Prevents Left Ventricular Remodeling and Failure After Experimental Myocardial Infarction in Mice : Role of Oxidative Stress Circ. Res., September 1, 2000; 87(5): 392 - 398. [Abstract] [Full Text] [PDF]
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L. Lu, Z. Gunja-Smith, J. F. Woessner, P. C. Ursell, T. Nissen, R. E. Galardy, Y. Xu, P. Zhu, and G. G. Schwartz Matrix metalloproteinases and collagen ultrastructure in moderate myocardial ischemia and reperfusion in vivo Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H601 - H609. [Abstract] [Full Text] [PDF]
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D. A. Siwik, D. L.-F. Chang, and W. S. Colucci Interleukin-1{beta} and Tumor Necrosis Factor-{alpha} Decrease Collagen Synthesis and Increase Matrix Metalloproteinase Activity in Cardiac Fibroblasts In Vitro Circ. Res., June 23, 2000; 86(12): 1259 - 1265. [Abstract] [Full Text] [PDF]
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Y. Y. Li, C. F. McTiernan, and A. M. Feldman Interplay of matrix metalloproteinases, tissue inhibitors of metalloproteinases and their regulators in cardiac matrix remodeling Cardiovasc Res, May 1, 2000; 46(2): 214 - 224. [Abstract] [Full Text] [PDF]
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