on July 18, 2005
Published online before print July 18, 2005, doi: 10.1161/CIRCULATIONAHA.104.531616
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Submitted on December 23, 2004
From the Departments of Pharmacology (G.S., J.S., M.S., C.J.S., R.S.), Pediatrics (H.L., R.S.), and Biochemistry (P.G.S.), Cardiovascular Research Group, University of Alberta, Edmonton, Alberta, Canada, and Department of Molecular and Cellular Pharmacology (D.S.-C.), University of Miami School of Medicine, Miami, Fla. * To whom correspondence should be addressed. E-mail: richard.schulz{at}ualberta.ca.
Background--Matrix metalloproteinase-2 (MMP-2) contributes to cardiac dysfunction resulting from ischemia-reperfusion (I/R) injury. MMP-2 not only remodels the extracellular matrix but also acts intracellularly in I/R by degrading troponin I. Whether other intracellular targets exist for MMP-2 during I/R is unknown. Methods and Results--Isolated rat hearts were subjected to 20 minutes of ischemia and 30 minutes of reperfusion. The impaired recovery of mechanical function of the heart was attenuated by the MMP inhibitors o-phenanthroline or doxycycline. Quantitative 2D electrophoresis of homogenates of aerobically perfused hearts (control) or those subjected to I/R injury (in the presence or absence of MMP inhibitors) showed 3 low-molecular-weight proteins with levels that were significantly increased upon I/R injury and normalized to control levels by MMP inhibitors. Mass spectrometry analysis identified all 3 proteins as fragments of myosin light chain 1, which possesses theoretical cleavage recognition sequences for MMP-2 and is rapidly degraded by it in vitro. The association of MMP-2 with the thick myofilament in fractions prepared from I/R hearts was observed with immunogold electron microscopy, gelatin zymography for MMP-2 activity, and immunoprecipitation. MMP-2 was found to cleave myosin light chain 1 between tyrosine 189 and glutamine 190 at the C terminus. Conclusions--Our results demonstrate that myosin light chain 1 is another novel substrate for MMP-2 in the cardiomyocyte and that its degradation may contribute to contractile dysfunction resulting from I/R injury to the heart.
Revised on April 12, 2005
Accepted on April 14, 2005
Degradation of Myosin Light Chain in Isolated Rat Hearts Subjected to Ischemia-Reperfusion Injury. A New Intracellular Target for Matrix Metalloproteinase-2
Grzegorz Sawicki PhD,
Key words: proteins • myocardial stunning • metalloproteinases • myosin • reperfusion
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