Published Online
on February 21, 2005

A more recent version of this article appeared on March 8, 2005

This Article Full Text (PDF) All Versions of this Article: 111/9/1166    most recent 01.CIR.0000157149.71297.3Av1 Alert me when this article is cited Alert me if a correction is posted 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 Deschamps, A. M. Articles by Spinale, F. G. Search for Related Content PubMed PubMed Citation Articles by Deschamps, A. M. Articles by Spinale, F. G. Pubmed/NCBI databases Gene Protein UniGene Compound via MeSH Substance via MeSH Medline Plus Health Information Cardiomyopathy Related Collections Structure Animal models of human disease Cell biology/structural biology Oxidant stress

Submitted on June 19, 2004
Revised on October 26, 2004
Accepted on November 3, 2004

Trafficking of the Membrane Type-1 Matrix Metalloproteinase in Ischemia and Reperfusion. Relation to Interstitial Membrane Type-1 Matrix Metalloproteinase Activity

Anne M. Deschamps BS, William M. Yarbrough MD, Christina E. Squires BS, Rebecca A. Allen BA, David M. McClister BS, HTL, Kathryn B. Dowdy BS, Julie E. McLean BS, Joseph T. Mingoia BS, Jeffrey A. Sample BS, Rupak Mukherjee PhD, and Francis G. Spinale MD, PhD^*

From the Division of Cardiothoracic Surgery, Medical University of South Carolina, and the Ralph H. Johnson Veteran’s Affairs Medical Center, Charleston, SC.

^* To whom correspondence should be addressed. E-mail: wilburnm{at}musc.edu.

Background--The matrix metalloproteinases (MMPs) contribute to regional remodeling after prolonged periods of ischemia and reperfusion (I/R), but specific MMP types activated during this process remain poorly understood. A novel class, the membrane-type MMPs (MT-MMPs), has been identified in the myocardium, but activity of these MMP types has not been assessed in vivo, particularly during I/R.

Methods and Results--Pigs (30 kg, n=8) were instrumented with microdialysis catheters to measure MT1-MMP activity in both ischemic and nonischemic (remote) myocardium. A validated MT1-MMP fluorogenic substrate was infused through the microdialysis system, and changes in fluorescence were reflective of MT1-MMP activity at steady state, during ischemia (90 minutes), and during reperfusion (120 minutes). At peak ischemia, MT1-MMP activity was increased by >40% in the ischemic region, with no change in the remote region, which persisted with reperfusion (P<0.05). After I/R, MT1-MMP abundance was increased by >50% (P<0.05). Differential centrifugation revealed that the endosomal fraction (which contains subcellular organelles) within the ischemic myocardium was associated with a >135% increase in MT1-MMP (P<0.05). Furthermore, in an isolated left ventricular myocyte model of I/R, hypoxia (simulated ischemia) induced a >70% increase in MT1-MMP abundance in myocytes, and confocal microscopy revealed MT1-MMP internalization during this time period and reemergence to the membrane with reperfusion.

Conclusions--These unique results demonstrate that a specific MMP type, MT1-MMP, is increased in abundance and activity with I/R and is likely attributed, at least in part, to changes in intracellular trafficking.

Key words: ischemia • metalloproteinases • myocytes • remodeling • reperfusion

This article has been cited by other articles:

				F. G. Spinale, G. P. Escobar, R. Mukherjee, J. A. Zavadzkas, S. M. Saunders, L. B. Jeffords, A. M. Leone, C. Beck, S. Bouges, and R. E. Stroud Cardiac-Restricted Overexpression of Membrane Type-1 Matrix Metalloproteinase in Mice: Effects on Myocardial Remodeling With Aging Circ Heart Fail, July 1, 2009; 2(4): 351 - 360. [Abstract] [Full Text] [PDF]

				J. A. Zavadzkas, R. A. Plyler, S. Bouges, C. N. Koval, W. T. Rivers, C. U. Beck, E. I. Chang, R. E. Stroud, R. Mukherjee, and F. G. Spinale Cardiac-restricted overexpression of extracellular matrix metalloproteinase inducer causes myocardial remodeling and dysfunction in aging mice Am J Physiol Heart Circ Physiol, October 1, 2008; 295(4): H1394 - H1402. [Abstract] [Full Text] [PDF]

				F. G. Spinale, C. N. Koval, A. M. Deschamps, R. E. Stroud, and J. S. Ikonomidis Dynamic Changes in Matrix Metalloprotienase Activity Within the Human Myocardial Interstitium During Myocardial Arrest and Reperfusion Circulation, September 30, 2008; 118(14_suppl_1): S16 - S23. [Abstract] [Full Text] [PDF]

				F. Schneider, G. K. Sukhova, M. Aikawa, J. Canner, N. Gerdes, S.-M. T. Tang, G.-P. Shi, S. S. Apte, and P. Libby Matrix Metalloproteinase-14 Deficiency in Bone Marrow-Derived Cells Promotes Collagen Accumulation in Mouse Atherosclerotic Plaques Circulation, February 19, 2008; 117(7): 931 - 939. [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]

				F. G. Spinale Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function Physiol Rev, October 1, 2007; 87(4): 1285 - 1342. [Abstract] [Full Text] [PDF]

				L. S. Spruill, A. S. Lowry, R. E. Stroud, C. E. Squires, I. M. Mains, E. C. Flack, C. Beck, J. S. Ikonomidis, A. J. Crumbley, P. J. McDermott, et al. Membrane-type-1 matrix metalloproteinase transcription and translation in myocardial fibroblasts from patients with normal left ventricular function and from patients with cardiomyopathy Am J Physiol Cell Physiol, October 1, 2007; 293(4): C1362 - C1373. [Abstract] [Full Text] [PDF]

				H. Nagase, R. Visse, and G. Murphy Structure and function of matrix metalloproteinases and TIMPs Cardiovasc Res, February 15, 2006; 69(3): 562 - 573. [Abstract] [Full Text] [PDF]

				A. M. Manso, L. Elsherif, S.-M. Kang, and R. S. Ross Integrins, membrane-type matrix metalloproteinases and ADAMs: Potential implications for cardiac remodeling Cardiovasc Res, February 15, 2006; 69(3): 574 - 584. [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]

				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]

				A. M. Deschamps, K. A. Apple, A. H. Leonardi, J. E. McLean, W. M. Yarbrough, R. E. Stroud, L. L. Clark, J. A. Sample, and F. G. Spinale Myocardial Interstitial Matrix Metalloproteinase Activity Is Altered by Mechanical Changes in LV Load: Interaction With the Angiotensin Type 1 Receptor Circ. Res., May 27, 2005; 96(10): 1110 - 1118. [Abstract] [Full Text] [PDF]