MG53 participates in ischaemic postconditioning through the RISK signalling pathway

Zhang, Yan; Lv, Fengxiang; Jin, Li; Peng, Wei; Song, Ruisheng; Ma, Jianjie; Cao, Chunmei; Xiao, Rui‐Ping

doi:10.1093/cvr/cvr029

Cited by 71 publications

(92 citation statements)

References 21 publications

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“…We and others have previously shown that MG53 is involved in striated muscle membrane repair, 14,15 and participates in ischemic preconditioning-and postconditioning-mediated cardiac protection. 16,17 Although all the studies, to date, have concentrated on the cytosolic functions of MG53, its role in the nucleus remains elusive. It is noteworthy that several members of the TRIM family play important roles in transcriptional regulation.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, we and others have reported that MG53 is abundantly expressed in the heart as well as skeletal muscle and involved in ischemia-mediated cardiac preconditioning and postconditioning. 16,17 But it is unclear whether MG53 plays a role in the regulation of myocardial glucose and lipid metabolism. In particular, we seek to determine the potential function of MG53 in regulating myocardial lipid metabolism and its malfunction in the pathogenesis of diabetic cardiomyopathy.…”

Section: Editorial See P 771 Clinical Perspective On P 804mentioning

confidence: 99%

“…16,17 Although all the studies, to date, have concentrated on the cytosolic functions of MG53, its role in the nucleus remains elusive. It is noteworthy that several members of the TRIM family play important roles in transcriptional regulation.…”

Section: Mg53 Induces Diabetic Cardiomyopathy Via Ppar-α 803mentioning

confidence: 99%

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Upregulation of MG53 Induces Diabetic Cardiomyopathy Through Transcriptional Activation of Peroxisome Proliferation-Activated Receptor α

et al. 2015

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Diabetes mellitus is an emerging global threat to human health. It is estimated that the total number of people experiencing diabetes mellitus will reach 366 million in 2030. 1 Although hypertension and coronary narrowing are major pathogenic factors of acquired cardiomyopathy, diabetes mellitus has been established as an independent risk factor since 1972.2 Diabetic cardiomyopathy, as a major complication, is the leading cause of morbidity and mortality for diabetic patients. Epidemiological studies have demonstrated that diabetic people have a 2-to 5-fold increase of risk in developing heart failure compared with age-matched healthy subjects after adjusting for age, blood pressure, weight, cholesterol level, and coronary artery disease. 3-7 Editorial see p 771 Clinical Perspective on p 804Rodent models are of particular value in study of diabetic cardiomyopathy because there is minimal confounding involvement of coronary atherosclerosis. It has been demonstrated that diabetic mice and rats fed with high-fat diet display cardiac remodeling and dysfunction. [8][9][10][11] Recently we and others have shown that mice overexpressing Mitsugumin 53 (MG53) Background-Diabetic cardiomyopathy, which contributes to >50% diabetic death, is featured by myocardial lipid accumulation, hypertrophy, fibrosis, and cardiac dysfunction. The mechanism underlying diabetic cardiomyopathy is poorly understood. Recent studies have shown that a striated muscle-specific E3 ligase Mitsugumin 53 (MG53, or TRIM72) constitutes a primary causal factor of systemic insulin resistance and metabolic disorders. Although it is most abundantly expressed in myocardium, the biological and pathological roles of MG53 in triggering cardiac metabolic disorders remain elusive. Methods and Results-Here we show that cardiac-specific transgenic expression of MG53 induces diabetic cardiomyopathy in mice. Specifically, MG53 transgenic mouse develops severe diabetic cardiomyopathy at 20 weeks of age, as manifested by insulin resistance, compromised glucose uptake, increased lipid accumulation, myocardial hypertrophy, fibrosis, and cardiac dysfunction. Overexpression of MG53 leads to insulin resistant via destabilizing insulin receptor and insulin receptor substrate 1. More importantly, we identified a novel role of MG53 in transcriptional upregulation of peroxisome proliferation-activated receptor alpha and its target genes, resulting in lipid accumulation and lipid toxicity, thereby contributing to diabetic cardiomyopathy. Conclusions-Our results suggest that overexpression of myocardial MG53 is sufficient to induce diabetic cardiomyopathy via dual mechanisms involving upregulation of peroxisome proliferation-activated receptor alpha and impairment of insulin signaling. These findings not only reveal a novel function of MG53 in regulating cardiac peroxisome proliferation-activated receptor alpha gene expression and lipid metabolism, but also underscore MG53 as an important therapeutic target for diabetes mellitus and associated cardiomyopathy. develop obes...

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Section: Discussionmentioning

confidence: 99%

Section: Editorial See P 771 Clinical Perspective On P 804mentioning

confidence: 99%

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Upregulation of MG53 Induces Diabetic Cardiomyopathy Through Transcriptional Activation of Peroxisome Proliferation-Activated Receptor α

et al. 2015

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“…RISK pathway (21)(22)(23) (Figure 2). It will provide a novel cardioprotective therapeutic strategy for the treatment of acute myocardial infarction.…”

Section: Reperfusion Injury Salvage Kinase Pathwaymentioning

confidence: 99%

Impaired RISK-GSK3β Pathway is Responsible for Comorbidities by Suppressing the Conditioning Cardioprotection

Jin¹,

Zhang²

2016

J Anesth Perioper Med

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Aim of review:This review elaborates the role of reperfusion injury salvage kinase and glycogen synthase kinase 3β (RISK-GSK3β) pathway in myocardial ischemia/reperfusion injury (IRI) and whether its impairment is responsible for comorbidities due to the suppression of the conditioning cardioprotection. Method: We review the articles about RISK-GSK3β pathway in myocardial IRI published in the last two decades. Recent findings: The RISK, including phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) and extracellular signal regulated kinase 1/2 (ERK1/2), combines with the downstream target of GSK3β, which confers important role in the conditioning cardioprotection when activated specifically at the time of myocardial reperfusion. Unfortunately, the conditioning protection is weakened or abolished when equipped with comorbidities such as aging, diabetes, obesity, as well as heart diseases. It has been speculated that the pathological processes resulting in RISK-GSK3β pathway alterations may affect the development of IRI and the responses to conditioning. Summary: The impairment of RISK-GSK3β pathway is responsible for the reduction of conditioning cardioprotection and any strategy that repairs the impairment may have the potential to restore the conditioning against the IRI in the heart in the state of comorbidities.

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“…A recent study showed that recombinant Trim72 protein provides therapeutic benefits for skeletal muscle myo-necrosis following damage due to vigorous exercise [17] . Moreover, it has also been shown that Trim72 plays a cardioprotective role following ischemia-reperfusion injury [18] . However, the molecular mechanism of Trim72 has not yet been extensively studied in cardiac fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

Tripartite Motif Protein 72 Regulates the Proliferation and Migration of Rat Cardiac Fibroblasts via the Transforming Growth Factor-β Signaling Pathway

Zhao

Liang²

2016

Cardiology

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Background: The proliferation and migration of cardiac fibroblasts are critical for the progress of cardiac fibrosis. Tripartite motif protein 72 (Trim72), also known as MG53, mediates the dynamic process of membrane fusion and exocytosis in striated muscle. However, the role of Trim72 in the proliferation and migration of cardiac fibroblasts is unknown. Methods: In the present study, we used small interference RNA (siRNA) to silence Trim72 and then investigated the effects of Trim72 on cardiac fibroblast proliferation and migration, which were activated during cardiac remodeling after myocardial infarction. Cardiac fibroblasts were isolated from 2- to 3-day-old neonatal Sprague-Dawley rats and transfected with siRNA. A cell-counting assay was used to determine the proliferation of cardiac fibroblasts. A Boyden chamber assay was performed to determine the migration of cardiac fibroblasts. Results: Our study has, for the first time, demonstrated that Trim72 regulates the cell proliferation and migration of rat cardiac fibroblasts. Furthermore, the data from the gene expression profile microarray analysis indicate that Trim72 depletion can cause downregulation of the transforming growth factor (TGF)-β signaling pathway, suggesting that Trim72 regulates the proliferation and migration of cardiac fibroblasts probably via the TGF-β signaling pathway. Conclusions: We have demonstrated that Trim72 might play a pivotal role in the proliferation of neonatal rat cardiac fibroblasts, which could be a potential target for the treatment of cardiac fibrosis. However, the involvement of other signaling pathways and factors in the formation of cardiac fibrosis cannot be excluded.

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MG53 participates in ischaemic postconditioning through the RISK signalling pathway

Abstract: We conclude that MG53 participates in PostC-mediated cardioprotection largely through tethering CaV3 and PI3K and subsequent activation of the RISK pathway.

Cited by 71 publications

References 21 publications

Upregulation of MG53 Induces Diabetic Cardiomyopathy Through Transcriptional Activation of Peroxisome Proliferation-Activated Receptor α

Upregulation of MG53 Induces Diabetic Cardiomyopathy Through Transcriptional Activation of Peroxisome Proliferation-Activated Receptor α

Impaired RISK-GSK3β Pathway is Responsible for Comorbidities by Suppressing the Conditioning Cardioprotection

Tripartite Motif Protein 72 Regulates the Proliferation and Migration of Rat Cardiac Fibroblasts via the Transforming Growth Factor-β Signaling Pathway

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