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J Mol Cell Cardiol. 2016 May;94:153-161. doi: 10.1016/j.yjmcc.2016.04.004. Epub 2016 Apr 11.

Nuclear matrix metalloproteinase-2 in the cardiomyocyte and the ischemic-reperfused heart.

Author information

1
Department of Pharmacology, Cardiovascular Research Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada. Electronic address: baghirov@ualberta.ca.
2
Department of Pharmacology, Cardiovascular Research Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada; Department of Pediatrics, Cardiovascular Research Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada. Electronic address: bryan.g.hughes@gmail.com.
3
Department of Pharmacology, Cardiovascular Research Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada; Department of Pediatrics, Cardiovascular Research Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada. Electronic address: poirier1@ualberta.ca.
4
Department of Pharmacology, Cardiovascular Research Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada; Department of Pediatrics, Cardiovascular Research Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada. Electronic address: marciayuri.k@gmail.com.
5
Department of Pharmacology, Cardiovascular Research Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada; Department of Pediatrics, Cardiovascular Research Institute, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, Canada. Electronic address: richard.schulz@ualberta.ca.

Abstract

Matrix metalloproteinases (MMPs) are zinc-dependent proteases involved in intra- and extra-cellular matrix remodeling resulting from oxidative stress injury to the heart. MMP-2 was the first MMP to be localized to the nucleus; however, its biological functions there are unclear. We hypothesized that MMP-2 is present in the nucleus under normal physiological conditions but increases during myocardial ischemia-reperfusion (I/R) injury-induced oxidative stress, proteolyzing nuclear structural proteins. Lamins are intermediate filament proteins that provide structural support to the nucleus and are putative targets of MMP-2. To identify lamin susceptibility to MMP-2 proteolysis, purified lamin A or B was incubated with MMP-2 in vitro. Lamin A, but not lamin B, was proteolysed by MMP-2 into an approximately 50kDa fragment, which was also predicted by in silico cleavage site analysis. Immunofluorescent confocal microscopy and subcellular fractionation showed MMP-2 both in the cytosol and nuclei of neonatal rat ventricular myocytes. Rat hearts were isolated and perfused by the Langendorff method aerobically, or subjected to I/R injury in the presence or absence of o-phenanthroline, an MMP inhibitor. Nuclear fractions extracted from I/R hearts showed increased MMP-2 activity, but not protein level. The level of troponin I, a known sarcomeric target of MMP-2, was rescued in I/R hearts treated with o-phenanthroline, demonstrating the efficacy of MMP inhibition. However, lamin A or B levels remained unchanged in I/R hearts. MMP-2 has a widespread subcellular distribution in cardiomyocytes, including a significant presence in the nucleus. The increase in nuclear MMP-2 activity seen during stunning injury here, indicates yet unknown biological actions, other than lamin proteolysis, which may require more severe ischemia to effect.

KEYWORDS:

Lamin; Matrix metalloproteinase-2; Myocardial ischemia; Nucleus; Proteolysis; Reperfusion

PMID:
27079252
DOI:
10.1016/j.yjmcc.2016.04.004
[Indexed for MEDLINE]

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