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

Lovett, David H.; Chu, Charles C.; Wang, Guanying; Ratcliffe, Mark B.; Baker, Anthony J.

doi:10.3389/fphys.2014.00363

Cited by 24 publications

(21 citation statements)

References 24 publications

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“…28, 31 Full length MMP-2 transcription can be driven by IL-6 via the STAT signaling cascade and it is most probable that the decreases in FL-MMP-2 following FTY720 treatment are the result of inhibition of IL6 synthesis. 33, 34 The NTT-MMP-2 isoforms lacks a STAT binding site in the intronic promoter, which is the most probable explanation for the absence of a FTY720 inhibitory effect on this isoform.…”

Section: Discussionmentioning

confidence: 99%

Immunosuppression With FTY720 Reverses Cardiac Dysfunction in Hypomorphic ApoE Mice Deficient in SR-BI Expression That Survive Myocardial Infarction Caused by Coronary Atherosclerosis

Luk¹,

Kim²,

Li³

et al. 2016

Journal of Cardiovascular Pharmacology

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Aims We recently reported that immunosuppression with FTY720 improves cardiac function and extends longevity in Hypomorphic ApoE mice deficient in scavenger receptor Type-BI expression, also known as the HypoE/SR-BI−/− mouse model of diet-induced coronary atherosclerosis and myocardial infarction (MI). In this study we tested the impact of FTY720 on cardiac dysfunction in HypoE/SR-BI−/− mice that survive MI and subsequently develop chronic heart failure. Methods/Results HypoE/SR-BI−/− mice were bred to Mx1-Cre transgenic mice and offspring were fed a high fat diet (HFD) for 3.5 weeks to provoke hyperlipidemia, coronary atherosclerosis and recurrent MIs. In contrast to our previous study, hyperlipidemia was rapidly reversed by inducible Cre-mediated gene repair of the HypoE allele and switching mice to a normal chow diet. Mice that survived the period of HFD were subsequently given oral FTY720 in drinking water or not, and left ventricular (LV) function was monitored using serial echocardiography for up to 15 weeks. In untreated mice, LV performance progressively deteriorated. Although FTY720 treatment did not initially prevent a decline of heart function among mice six weeks after Cre-mediated gene repair, it almost completely restored normal LV function in these mice by 15 weeks. Reversal of heart failure did not result from reduced atherosclerosis as the burden of aortic and coronary atherosclerosis actually increased to similar levels in both groups of mice. Rather, FTY720 caused systemic immunosuppression as assessed by reduced numbers of circulating T and B lymphocytes. In contrast, FTY720 did not enhance the loss of T cells or macrophages that accumulated in the heart during the HFD feeding period, but it did enhance the loss of B cells soon after plasma lipid lowering. Moreover, FTY720 potently reduced the expression of matrix metalloproteinase-2 and genes involved in innate immunity-associated inflammation in the heart. Conclusions Our data demonstrate that immunosuppression with FTY720 prevents post-infarction myocardial remodeling and chronic heart failure.

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Section: Discussionmentioning

confidence: 99%

Immunosuppression With FTY720 Reverses Cardiac Dysfunction in Hypomorphic ApoE Mice Deficient in SR-BI Expression That Survive Myocardial Infarction Caused by Coronary Atherosclerosis

Luk¹,

Kim²,

Li³

et al. 2016

Journal of Cardiovascular Pharmacology

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“…13 Numerous studies have demonstrated increased levels of MMPs, especially MMP-2 and MMP-9, at sites of cardiovascular diseases, including hypertension. [23][24][25] Also it has been commonly observed that in ageing, fibrosis leads to increased passive stiffness in the myocardium and impaired diastolic dysfunction. Therefore, changes in the MMP and TIMP profile and the consequent effects on myocardial ECM are found in ageing.…”

Section: Discussionmentioning

confidence: 99%

Microcurrent stimulation promotes reverse remodelling in cardiomyocytes

et al. 2016

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AimsIt has been shown that electrical stimulation can improve tissue repair in patients. Imbalances in the extracellular matrix composition induce manifestation of heart failure. Here we investigated the application of microcurrent (MC) to modulate the expression of matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in cardiomyocytes in vitro and in vivo to reverse remodelling in the heart in spontaneous hypertensive rats (SHR).MethodsCardiomyocytes from young SHR (7 months) and old SHR (14 months) were stimulated in vitro and in vivo with MC. MMP and TIMP expression were analysed by qPCR and immunofluorescence to evaluate the modulation of MC treatment.ResultsModulation of cardiomyocytes with MC enhances proliferation with no morphological changes in vitro. By electrical stimulation dual effects, increase and decrease, on MMP‐2, MMP‐9, TIMP‐3, and TIMP‐4 mRNA as well as protein expression were observed, depending on the age of the cardiomyocytes. In our in vivo study, MC down‐regulated MMP‐2, MMP‐9, and TIMP‐4 and increased TIMP‐3 in young SHR. In old SHR MMP‐2, MMP‐9, and TIMP‐4 were up‐regulated, whereas TIMP‐3 was unaffected.ConclusionsOur data indicate that treatment of MC can modulate the expression of MMPs and TIMPs in vitro and in vivo in SHR. Based on these results new treatments for heart failure could be developed.

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“…We have validated the specificity of the poly-clonal anti-NTT-MMP-2 antibody in our previous studies. 19,24 Slides were then incubated in biotinylated rabbit anti-goat secondary antibody for 30 min. After incubating with Vectastain ABC reagent for…”

Section: Quantitative Polymerase Chain Reaction (Qpcr)mentioning

confidence: 99%

“…NTT‐MMP‐2 activates a primary innate immune response with enhanced transcription of genes characteristic of a Type I interferon response resulting in inflammation and cellular necrosis . Recent studies have suggested that many pathological functions of MMP‐2 are mediated by NTT‐MMP‐2 rather than FL‐MMP‐2 …”

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confidence: 99%

“…18 Recent studies have suggested that many pathological functions of MMP-2 are mediated by NTT-MMP-2 rather than FL-MMP-2. [17][18][19] The goal of the current study was to evaluate the contribution of NTT-MMP-2 in skeletal muscle IRI. Based on its contribution to tissue damage seen in Sunil K. Joshi other IRI models, we hypothesized that NTT-MMP-2 is the major isoform associated with skeletal muscle IRI.…”

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confidence: 99%

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Novel intracellular N‐terminal truncated matrix metalloproteinase‐2 isoform in skeletal muscle ischemia‐reperfusion injury

Joshi

Lee

Lovett

et al. 2015

Journal Orthopaedic Research

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Ischemia-reperfusion injury (IRI) occurs when blood returns to tissues following a period of ischemia. Reintroduction of blood flow results in the production of free radicals and reactive oxygen species that damage cells. Skeletal muscle IRI is commonly seen in orthopedic trauma patients. Experimental studies in other organ systems have elucidated the importance of extracellular and intracellular matrix metalloproteinase-2 (MMP-2) isoforms in regulating tissue damage in the setting of oxidant stress resulting from IRI. Although the extracellular full-length isoform of MMP-2 (FL-MMP-2) has been previously studied in the setting of skeletal muscle IRI, studies investigating the role of the N-terminal truncated isoform (NTT-MMP-2) in this setting are lacking. In this study, we first demonstrated significant increases in FL-and NTT-MMP-2 gene expression in C2C12 myoblast cells responding to re-oxygenation following hypoxia in vitro. We then evaluated the expression of FL-and NTT-MMP-2 in modulating skeletal muscle IRI using a previously validated murine model. NTT-MMP-2, but not FL-MMP-2 expression was significantly increased in skeletal muscle following IRI. Moreover, the expression of toll-like receptors (TLRs) -2 and -4, IL-6, OAS-1A, and CXCL1 was also significantly up-regulated following IRI. Treatment with the potent anti-oxidant pyrrolidine dithiocarbamate (PDTC) significantly suppressed NTT-MMP-2, but not FL-MMP-2 expression and improved muscle viability following IRI. This data suggests that NTT-MMP-2, but not FL-MMP-2, is the major isoform of MMP-2 involved in skeletal muscle IRI. ß

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

Cited by 24 publications

References 24 publications

Immunosuppression With FTY720 Reverses Cardiac Dysfunction in Hypomorphic ApoE Mice Deficient in SR-BI Expression That Survive Myocardial Infarction Caused by Coronary Atherosclerosis

Immunosuppression With FTY720 Reverses Cardiac Dysfunction in Hypomorphic ApoE Mice Deficient in SR-BI Expression That Survive Myocardial Infarction Caused by Coronary Atherosclerosis

Microcurrent stimulation promotes reverse remodelling in cardiomyocytes

Novel intracellular N‐terminal truncated matrix metalloproteinase‐2 isoform in skeletal muscle ischemia‐reperfusion injury

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