Mechanisms of cytosolic targeting of matrix metalloproteinase‐2

Ali, Mohammad; Chow, Ava K.; Kandasamy, Arulmozhi D.; Fan, Xiaohu; West, Lori J.; Crawford, Bryan D.; Simmen, Thomas; Schulz, Richard

doi:10.1002/jcp.24040

Cited by 78 publications

(88 citation statements)

References 33 publications

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“…However, recent studies have recognized that FL-MMP-2 is also an intracellular protease (Schulz, 2007), with almost 40% of newly synthesized FL-MMP-2 retained in the cytosol due to an inefficient secretory signal (Ali et al, 2012). In the setting of oxidative stress, intracellular FL-MMP-2 is activated by release of the inhibitory prodomain, leading to FL-MMP-2-mediated cleavage of sarcomeric proteins with resultant contractile dysfunction (Schulz, 2007).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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“…In the cardiovascular system, the matrix metalloproteinases (MMPs), especially MMP-2, are abundantly expressed in cardiomyocytes [14]. Besides the well-known extracellular localization and substrates of MMP-2, it is also a bona fide intracellular protease [15] which is also localized to specific subcellular compartments in the cardiomyocyte, including the sarcomere [14] and nucleus [16]. Upon its direct activation by increased oxidative stress [17,18] MMP-2 cleaves specific intracellular proteins including its substrates in the sarcomere such as α-actinin [19], troponin I [14], myosin light chain-1 [20], titin [21] and GSK-3β [22].…”

Section: Introductionmentioning

confidence: 99%

Dynamic Alterations to α-Actinin Accompanying Sarcomere Disassembly and Reassembly during Cardiomyocyte Mitosis

et al. 2015

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Although mammals are thought to lose their capacity to regenerate heart muscle shortly after birth, embryonic and neonatal cardiomyocytes in mammals are hyperplastic. During proliferation these cells need to selectively disassemble their myofibrils for successful cytokinesis. The mechanism of sarcomere disassembly is, however, not understood. To study this, we performed a series of immunofluorescence studies of multiple sarcomeric proteins in proliferating neonatal rat ventricular myocytes and correlated these observations with biochemical changes at different cell cycle stages. During myocyte mitosis, α-actinin and titin were disassembled as early as prometaphase. α-actinin (representing the sarcomeric Z-disk) disassembly precedes that of titin (M-line), suggesting that titin disassembly occurs secondary to the collapse of the Z-disk. Sarcomere disassembly was concurrent with the dissolution of the nuclear envelope. Inhibitors of several intracellular proteases could not block the disassembly of α-actinin or titin. There was a dramatic increase in both cytosolic (soluble) and sarcomeric α-actinin during mitosis, and cytosolic α-actinin exhibited decreased phosphorylation compared to sarcomeric α-actinin. Inhibition of cyclin-dependent kinase 1 (CDK1) induced the quick reassembly of the sarcomere. Sarcomere dis- and re-assembly in cardiomyocyte mitosis is CDK1-dependent and features dynamic differential post-translational modifications of sarcomeric and cytosolic α-actinin.

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“…The majority of MMP-2 synthesized is secreted (~60%) acting in a paracrine manner, with the remaining 40% being targeted to the cytosol [22] or mitochondrial associated membranes [23]. Therefore, it is possible that MMP-2 originating in endothelium, smooth muscle cells, or fibroblasts is upregulated in response to oxidative stress and can act in a paracrine manner on cardiomyocytes, contributing to the development of I/R injury and cardiac contractile dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of MMP-2 Expression with siRNA Increases Baseline Cardiomyocyte Contractility and Protects against Simulated Ischemic Reperfusion Injury

Lin

Cadete

Sra

et al. 2014

BioMed Research International

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Matrix metalloproteinases (MMPs) significantly contribute to ischemia reperfusion (I/R) injury, namely, by the degradation of contractile proteins. However, due to the experimental models adopted and lack of isoform specificity of MMP inhibitors, the cellular source and identity of the MMP(s) involved in I/R injury remain to be elucidated. Using isolated adult rat cardiomyocytes, subjected to chemically induced I/R-like injury, we show that specific inhibition of MMP-2 expression and activity using MMP-2 siRNA significantly protected cardiomyocyte contractility from I/R-like injury. This was also associated with increased expression of myosin light chains 1 and 2 (MLC1/2) in comparison to scramble siRNA transfection. Moreover, the positive effect of MMP-2 siRNA transfection on cardiomyocyte contractility and MLC1/2 expression levels was also observed under control conditions, suggesting an important additional role for MMP-2 in physiological sarcomeric protein turnover. This study clearly demonstrates that intracellular expression of MMP-2 plays a significant role in sarcomeric protein turnover, such as MLC1 and MLC2, under aerobic (physiological) conditions. In addition, this study identifies intracellular/autocrine, cardiomyocyte-produced MMP-2, rather than paracrine/extracellular, as responsible for the degradation of MLC1/2 and consequent contractile dysfunction in cardiomyocytes subjected to I/R injury.

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Mechanisms of cytosolic targeting of matrix metalloproteinase‐2

Cited by 78 publications

References 33 publications

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

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

Dynamic Alterations to α-Actinin Accompanying Sarcomere Disassembly and Reassembly during Cardiomyocyte Mitosis

Inhibition of MMP-2 Expression with siRNA Increases Baseline Cardiomyocyte Contractility and Protects against Simulated Ischemic Reperfusion Injury

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