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(Circulation. 2005;111:1166-1174.)
© 2005 American Heart Association, Inc.

Molecular Cardiology

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; 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.

Correspondence to Francis. G. Spinale, MD, PhD, Cardiothoracic Surgery, Room 625, Strom Thurmond Research Bldg, 114 Doughty St, Medical University of South Carolina, Charleston, SC 29403. E-mail wilburnm{at}musc.edu

Received June 19, 2004; revision received October 26, 2004; accepted November 3, 2004.

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

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