A Novel Intracellular Isoform of Matrix Metalloproteinase-2 Induced by Oxidative Stress Activates Innate Immunity

Lovett, David H.; Mahimkar, Rajeev; Raffaı̈, Robert L.; Cape, Leslie; Maklashina, Elena; Cecchini, Gary; Karliner, Joel S.

doi:10.1371/journal.pone.0034177

Cited by 99 publications

(132 citation statements)

References 67 publications

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“…However, there is evidence for intracellular actions of MMPs that hold relevance to LV remodeling and the progression to HF. 35,146,147,156 For example, MMP-2 has been localized to cardiocyte mitochondria and was inducible by oxidative stress. Moreover, this past study identified different MMP-2 isoforms existing within the intracellular matrix as opposed to the ECM.…”

Section: Mmp Proteolysis and Profibrosis: Two Sides Of The Same Coinmentioning

confidence: 99%

“…Moreover, this past study identified different MMP-2 isoforms existing within the intracellular matrix as opposed to the ECM. 156 Thus, not only is there an ever growing number of MMP types that are expressed within the myocardial with LV remodeling, but there may also be isoforms for each of these MMP types. These discrete MMP expression-localization patterns would hold relevance in terms of substrate processing, whereby a number of intracellular substrates, both of the cytoskeletal and contractile protein domains, have been identified by degradomic profiling.…”

Section: Mmp Proteolysis and Profibrosis: Two Sides Of The Same Coinmentioning

confidence: 99%

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Membrane-Associated Matrix Proteolysis and Heart Failure

Spinale

Janicki²,

Zile³

2013

Circ Res

141

132

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The extracellular matrix (ECM) is a complex entity containing a large portfolio of structural proteins, signaling molecules, and proteases. Changes in the overall integrity and activational state of these ECM constituents can contribute to tissue structure and function, which is certainly true of the myocardium. Changes in the expression patterns and activational states of a family of ECM proteolytic enzymes, the matrix metalloproteinases (MMPs), have been identified in all forms of LV remodeling and can be a contributory factor for the progression to heart failure. However, new clinical and basic research has identified some surprising and unpredicted changes in MMP profiles in LV remodeling processes, such as with pressure or volume overload, as well as with myocardial infarction. From these studies, it has become recognized that proteolytic processing of signaling molecules by certain MMP types, particularly the transmembrane MMPs, may actually facilitate ECM accumulation as well as modulate fibroblast transdifferentiation – both critical events in adverse LV remodeling. Based upon the ever increasing substrates and diversity of biological actions of MMPs, it is likely that continued research regarding the relationship of LV remodeling to this family of proteases will yield new insights into the ECM remodeling process itself as well as new therapeutic targets.

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Section: Mmp Proteolysis and Profibrosis: Two Sides Of The Same Coinmentioning

confidence: 99%

Section: Mmp Proteolysis and Profibrosis: Two Sides Of The Same Coinmentioning

confidence: 99%

Membrane-Associated Matrix Proteolysis and Heart Failure

Spinale

Janicki²,

Zile³

2013

Circ Res

141

132

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“…Oxidative stress-mediated generation of NTT-MMP-2 may contribute to progressive cardiac dysfunction in the setting of ischemia (Lovett et al, 2012). Translation of the NTT-MMP-2 transcript is initiated at Methionine 77 , resulting in an N-terminal truncated MMP-2 protein lacking the secretory sequence and the inhibitory prodomain.…”

Section: Introductionmentioning

confidence: 99%

A N-terminal truncated intracellular isoform of matrix metalloproteinase-2 impairs contractility of mouse myocardium

et al. 2014

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The full-length isoform of matrixmetalloproteinase-2 (FL-MMP-2) plays a role in turnover of the cardiac extracellular matrix. FL-MMP-2 is also present intracellularly in association with sarcomeres and, in the setting of oxidative stress, cleaves myofilament proteins with resultant impaired contractility. Recently, a novel N-terminal truncated MMP-2 isoform (NTT-MMP-2) generated during oxidative stress was identified and shown to induce severe systolic failure; however, the injury mechanisms remained unclear. In this study, cardiac-specific NTT-MMP-2 transgenic mice were used to determine the physiological effects of NTT-MMP-2 on: force development of intact myocardium; the function of cardiac myofilaments in demembranated myocardium; and on intracellular Ca2+ transients in isolated myocytes. We related the contractile defects arising from NTT-MMP-2 expression to the known intracellular locations of NTT-MMP-2 determined using immunohistochemistry. Comparison was made with the pathophysiology arising from cardiac-specific FL-MMP-2 transgenic mice. Consistent with previous studies, FL-MMP-2 was localized to myofilaments, while NTT-MMP-2 was concentrated within subsarcolemmal mitochondria and to sites in register with the Z-line. NTT-MMP-2 expression caused a 50% reduction of force development by intact myocardium. However, NTT-MMP-2 expression did not reduce myofilament force development, consistent with the lack of NTT-MMP-2 localization to myofilaments. NTT-MMP-2 expression caused a 50% reduction in the amplitude of Ca2+ transients, indicating impaired activation.Conclusions: Unlike FL-MMP-2, NTT-MMP-2 does not mediate myofilament damage. Instead, NTT-MMP-2 causes impaired myocyte activation, which may involve effects due to localization in mitochondria and/or to transverse tubules affecting Ca2+ transients. Thus, FL-MMP-2 and NTT-MMP-2 have discrete intracellular locations and mediate different intracellular damage to cardiac myocytes.

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“…It has also been reported that MMP-2 can be activated by reactive nitrogen species without proteolytic cleavage and removal of the pro-domain and hence gives rise to an allosterically activated MMP-2 with the same molecular weight as the proenzyme (Viappiani et al 2009). Furthermore, oxidative stress was recently found to induce generation of an intracellular MMP-2 isoform lacking both the N-terminal signal sequence as well as the inhibitory pro-domain (Lovett et al 2012). In cardiac myocytes, caspases have been found to be potential activators of MMP-2 after myocardial ischemia, and finally, MMP-2 activity may be regulated by phosphorylation (Cauwe and Opdenakker 2010).…”

Section: Discussionmentioning

confidence: 99%

Tissue- and Cell-Specific Co-localization of Intracellular Gelatinolytic Activity and Matrix Metalloproteinase 2

Solli

Fadnes

Winberg

et al. 2013

J Histochem Cytochem.

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Matrix metalloproteinase 2 (MMP-2) is a proteolytic enzyme that degrades extracellular matrix proteins. Recent studies indicate that MMP-2 also has a role in intracellular proteolysis during various pathological conditions, such as ischemic injuries in heart and brain and in tumor growth. The present study was performed to map the distribution of intracellular MMP-2 activity in various mouse tissues and cells under physiological conditions. Samples from normal brain, heart, lung, liver, spleen, pancreas, kidney, adrenal gland, thyroid gland, gonads, oral mucosa, salivary glands, esophagus, intestines, and skin were subjected to high-resolution in situ gelatin zymography and immunohistochemical staining. In hepatocytes, cardiac myocytes, kidney tubuli cells, epithelial cells in the oral mucosa as well as in excretory ducts of salivary glands, and adrenal cortical cells, we found strong intracellular gelatinolytic activity that was significantly reduced by the metalloprotease inhibitor EDTA but not by the cysteine protease inhibitor E-64. Furthermore, the gelatinolytic activity was co-localized with MMP-2. Western blotting and electron microscopy combined with immunogold labeling revealed the presence of MMP-2 in different intracellular compartments of isolated hepatocytes. Our results indicate that MMP-2 takes part in intracellular proteolysis in specific tissues and cells during physiological conditions.

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A Novel Intracellular Isoform of Matrix Metalloproteinase-2 Induced by Oxidative Stress Activates Innate Immunity

Cited by 99 publications

References 67 publications

Membrane-Associated Matrix Proteolysis and Heart Failure

Membrane-Associated Matrix Proteolysis and Heart Failure

A N-terminal truncated intracellular isoform of matrix metalloproteinase-2 impairs contractility of mouse myocardium

Tissue- and Cell-Specific Co-localization of Intracellular Gelatinolytic Activity and Matrix Metalloproteinase 2

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