This Article Full Text Full Text (PDF) All Versions of this Article: 107/19/2487    most recent 01.CIR.0000065603.09430.58v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Schulze, C. J. Articles by Schulz, R. Search for Related Content PubMed PubMed Citation Articles by Schulze, C. J. Articles by Schulz, R. Related Collections Contractile function Ischemic biology - basic studies

(Circulation. 2003;107:2487.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Imbalance Between Tissue Inhibitor of Metalloproteinase-4 and Matrix Metalloproteinases During Acute Myoctardial Ischemia-Reperfusion Injury

Costas J. Schulze, MD^*; Wenjie Wang, MD, PhD^*; Wilma L. Suarez-Pinzon, MSc; Jolanta Sawicka, MSc; Grzegorz Sawicki, PhD; Richard Schulz, PhD

From the Departments of Pharmacology (C.S., W.W., J.S., G.S., R.S.), Pediatrics (R.S.), and Medicine (W.L.S.-P.), Cardiovascular Research Group, University of Alberta, Edmonton, Canada.

Correspondence to Dr Richard Schulz, Departments of Pediatrics and Pharmacology, 4-62 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, T6G 2S2 Canada. E-mail richard.schulz{at}ualberta.ca

Background— We have previously reported that matrix metalloproteinase-2 (MMP-2) contributes to myocardial ischemia-reperfusion injury by degradation of troponin I, a regulatory element of the contractile proteins. MMP activities are also tightly regulated by tissue inhibitors of metalloproteinase (TIMPs). The change in TIMPs during acute myocardial ischemia-reperfusion injury is not clear.

Methods and Results— Isolated rat hearts were perfused either aerobically for 75 minutes or subjected to 15, 20, or 25 minutes of global, no-flow ischemia followed by 30 minutes of aerobic reperfusion. During reperfusion after ischemia, there was a rapid, enhanced release of TIMP-4, the most abundant TIMP in the heart, into the coronary effluent, as shown both by reverse zymography and Western blot. There was a negative correlation between the recovery of cardiac mechanical function and the release of TIMP-4 during reperfusion in hearts subjected to different durations of ischemia. Immunogold electron microscopy revealed a close association of TIMP-4 with the sarcomeres in aerobically perfused hearts. Moreover, TIMP-4 was present only in thin myofilaments prepared from aerobically perfused hearts but not in ischemic-reperfused hearts. An enhanced MMP activity was shown in ischemic-reperfused hearts by in situ zymography.

Conclusions— Loss of TIMP-4 from the cardiac myocyte leads to an increase in net myocardial MMP activity that contributes to acute myocardial stunning injury.

Key Words: ischemia • reperfusion • inhibitors • metalloproteinases

This article has been cited by other articles:

				A. D. Kandasamy, A. K. Chow, M. A.M. Ali, and R. Schulz Matrix metalloproteinase-2 and myocardial oxidative stress injury: beyond the matrix Cardiovasc Res, August 20, 2009; (2009) cvp268v2. [Abstract] [Full Text] [PDF]

				A. Sokal, M. Zembala, A. Radomski, A. Kocher, J. Pacholewicz, J. Los, E. Jedrzejczyk, M. Zembala, and M. Radomski A differential release of matrix metalloproteinases 9 and 2 during coronary artery bypass grafting and off-pump coronary artery bypass surgery. J. Thorac. Cardiovasc. Surg., May 1, 2009; 137(5): 1218 - 1224. [Abstract] [Full Text] [PDF]

				A. M. Deschamps, J. Zavadzkas, R. L. Murphy, C. N. Koval, J. E. McLean, L. Jeffords, S. M. Saunders, N. J. Sheats, R. E. Stroud, and F. G. Spinale Interruption of endothelin signaling modifies membrane type 1 matrix metalloproteinase activity during ischemia and reperfusion Am J Physiol Heart Circ Physiol, February 1, 2008; 294(2): H875 - H883. [Abstract] [Full Text] [PDF]

				H. Aupperle, J. Garbade, A. Schubert, M. Barten, S. Dhein, H.-A Schoon, and F.-W Mohr Effects of Autologous Stem Cells on Immunohistochemical Patterns and Gene Expression of Metalloproteinases and Their Tissue Inhibitors in Doxorubicin Cardiomyopathy in a Rabbit Model Vet. Pathol., July 1, 2007; 44(4): 494 - 503. [Abstract] [Full Text] [PDF]

				S. Janssens and H. R. Lijnen What has been learned about the cardiovascular effects of matrix metalloproteinases from mouse models? Cardiovasc Res, February 15, 2006; 69(3): 585 - 594. [Abstract] [Full Text] [PDF]

				K. Trescher, O. Bernecker, B. Fellner, M. Gyongyosi, R. Schafer, S. Aharinejad, R. DeMartin, E. Wolner, and B. K. Podesser Inflammation and postinfarct remodeling: Overexpression of I{kappa}B prevents ventricular dilation via increasing TIMP levels Cardiovasc Res, February 15, 2006; 69(3): 746 - 754. [Abstract] [Full Text] [PDF]

				M. D. Covington, R. C. Burghardt, and A. R. Parrish Ischemia-induced cleavage of cadherins in NRK cells requires MT1-MMP (MMP-14) Am J Physiol Renal Physiol, January 1, 2006; 290(1): F43 - F51. [Abstract] [Full Text] [PDF]

				M. Saghizadeh, A. A. Kramerov, J. Tajbakhsh, A. M. Aoki, C. Wang, N.-N. Chai, J. Y. Ljubimova, T. Sasaki, G. Sosne, M. R. J. Carlson, et al. Proteinase and Growth Factor Alterations Revealed by Gene Microarray Analysis of Human Diabetic Corneas Invest. Ophthalmol. Vis. Sci., October 1, 2005; 46(10): 3604 - 3615. [Abstract] [Full Text] [PDF]

				V. Mellin, M. Isabelle, A. Oudot, C. Vergely-Vandriesse, C. Monteil, B. Di Meglio, J. P. Henry, B. Dautreaux, L. Rochette, C. Thuillez, et al. Transient reduction in myocardial free oxygen radical levels is involved in the improved cardiac function and structure after long-term allopurinol treatment initiated in established chronic heart failure Eur. Heart J., August 1, 2005; 26(15): 1544 - 1550. [Abstract] [Full Text] [PDF]

				M. D. Covington, K. J. Bayless, R. C. Burghardt, G. E. Davis, and A. R. Parrish Ischemia-induced cleavage of cadherins in NRK cells: evidence for a role of metalloproteinases Am J Physiol Renal Physiol, August 1, 2005; 289(2): F280 - F288. [Abstract] [Full Text] [PDF]

				G. Sawicki, H. Leon, J. Sawicka, M. Sariahmetoglu, C. J. Schulze, P. G. Scott, D. Szczesna-Cordary, and R. Schulz Degradation of Myosin Light Chain in Isolated Rat Hearts Subjected to Ischemia-Reperfusion Injury: A New Intracellular Target for Matrix Metalloproteinase-2 Circulation, July 26, 2005; 112(4): 544 - 552. [Abstract] [Full Text] [PDF]

				J. Chen, C.-H. Tung, J. R. Allport, S. Chen, R. Weissleder, and P. L. Huang Near-Infrared Fluorescent Imaging of Matrix Metalloproteinase Activity After Myocardial Infarction Circulation, April 12, 2005; 111(14): 1800 - 1805. [Abstract] [Full Text] [PDF]

				A. M. Deschamps, W. M. Yarbrough, C. E. Squires, R. A. Allen, D. M. McClister, K. B. Dowdy, J. E. McLean, J. T. Mingoia, J. A. Sample, R. Mukherjee, et al. Trafficking of the Membrane Type-1 Matrix Metalloproteinase in Ischemia and Reperfusion: Relation to Interstitial Membrane Type-1 Matrix Metalloproteinase Activity Circulation, March 8, 2005; 111(9): 1166 - 1174. [Abstract] [Full Text] [PDF]

				J. D. Lovelock, A. H. Baker, F. Gao, J.-F. Dong, A. L. Bergeron, W. McPheat, N. Sivasubramanian, and D. L. Mann Heterogeneous effects of tissue inhibitors of matrix metalloproteinases on cardiac fibroblasts Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H461 - H468. [Abstract] [Full Text] [PDF]

				K. Kaikita, T. Hayasaki, T. Okuma, W. A. Kuziel, H. Ogawa, and M. Takeya Targeted Deletion of CC Chemokine Receptor 2 Attenuates Left Ventricular Remodeling after Experimental Myocardial Infarction Am. J. Pathol., August 1, 2004; 165(2): 439 - 447. [Abstract] [Full Text] [PDF]