Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte hypertrophy

Yamamoto, Shimako; Yang, Ge; Zablocki, Daniela; Liu, Jing; Hong, Chull; Kim, Song-Jung; Soler, Sandra; Odashima, Mari; Thaisz, Jill; Yehia, Ghassan; Molina, Carlos A.; Yatani, Atsuko; Vatner, Dorothy E.; Vatner, Stephen F.; Sadoshima, Junichi

doi:10.1172/jci17459

Cited by 254 publications

(347 citation statements)

References 49 publications

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“…More recent studies have suggested a cardinal role for MST1 in the development of cardiac dysfunction through inhibition of autophagy and facilitated accumulation of protein aggresomes [6]. Overexpression of MST1 initiates apoptosis, whereas inhibition of endogenous MST1 prevents apoptosis and cardiomyopathy in response to pathologically relevant stresses [11,12]. Interestingly, our recent studies have found suppressed autophagy and augmented apoptosis in diabetic hearts.…”

Section: Introductionmentioning

confidence: 67%

“…MST1 has been shown to serve as a key component of a multistep signalling pathway that controls the expression of genes associated with autophagy and apoptosis [6,[10][11][12]. More recent studies have suggested a cardinal role for MST1 in the development of cardiac dysfunction through inhibition of autophagy and facilitated accumulation of protein aggresomes [6].…”

Section: Introductionmentioning

confidence: 99%

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MST1 coordinately regulates autophagy and apoptosis in diabetic cardiomyopathy in mice

Zhang

et al. 2016

Diabetologia

113

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Aims/hypothesis Diabetic cardiomyopathy (DCM) is associated with suppressed autophagy and augmented apoptosis in the heart although the interplay between the two remains elusive. The ability of mammalian sterile 20-like kinase 1 to regulate both autophagy and apoptosis prompted us to investigate it as a possible candidate in the progression of DCM. Methods Wild-type, Mst1 (also known as Stk4) transgenic and Mst1-knockout mice were challenged with streptozotocin to induce experimental diabetes. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulated diabetes to probe mechanisms. Results Mst1 knockout alleviated while Mst1 overexpression aggravated cardiac dysfunction in diabetes. Diabetic Mst1 transgenic mice exhibited decreased LC3 expression and enhanced protein aggregation. In contrast, typical autophagosomes were observed in diabetic Mst1-knockout mice with increased LC3 expression and reduced protein aggregation. Mst1 downregulation promoted autophagic flux as demonstrated by increased LC3-II and decreased p62 expression in the presence of bafilomycin A1. Furthermore, Mst1 overexpression increased, while Mst1 knockout decreased, cardiomyocyte apoptosis both in vivo and in vitro. Coimmunoprecipitation assays showed that Mst1 overexpression promoted Beclin1 binding to B cell lymphoma 2 (Bcl-2) and induced dissociation of Bcl-2 from Bax in diabetic mice. Conversely, Mst1 knockout disrupted the Beclin1-Bcl-2 complex and enhanced the interaction between Bcl-2 and Bax. Conclusions/interpretation Mst1 knockout restores autophagy and protects against apoptosis in cardiomyocytes, en route to the rescue against DCM.

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Section: Introductionmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

MST1 coordinately regulates autophagy and apoptosis in diabetic cardiomyopathy in mice

Zhang

et al. 2016

Diabetologia

113

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“…3,9,12,36 In the present study, the infarct areas were measured by using Adobe Photoshop, the method was also used for measuring the infarct areas in the heart. 37 Many other image analysis softwares are used for measuring the infarct areas in different experiments. 3,12,14 In our experiment, two hours of MCAO in control animals resulted in the infarct volume of 217.3 ± 79.5 mm 3 (corrected infarct volume), which is similar with the infarct volume of 210.39 ± 31.25 mm 3 (corrected infarct volume) after two hours of MCAO in another report.…”

Section: Discussionmentioning

confidence: 99%

Neuroanesthesia and Intensive Care Isoflurane tolerance against focal cerebral ischemia is attenuated by adenosine A1 receptor antagonists

Liu

Xiong

Chen

et al. 2006

Can J Anesth/J Can Anesth

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Purpose:To investigate the role of the adenosine A 1 receptor in the rapid tolerance to cerebral ischemia induced by isoflurane preconditioning. Methods: Seventy-five rats were randomly assigned into five groups (n = 15 each): Control, 8-cyclopentyl-1,3-dipropulxanthine (DPCPX), Isoflurane, DPCPX+Isoflurane and Vehicle+Isoflurane groups. All animals underwent right middle cerebral artery occlusion (MCAO) for two hours. Isoflurane preconditioning was conducted one hour before MCAO in Isoflurane, DPCPX+Isoflurane and Vehicle+Isoflurane groups by exposing the animals to 1.5% isoflurane in 98% oxygen for one hour. In the Control and DPCPX groups, animals were exposed to 98% oxygen one hour before MCAO for one hour. A selective adenosine A 1 receptor antagonist, DPCPX, was administered (0.1 mg·kg -1 ) 15 min before isoflurane/oxygen exposure in the DPCPX and DPCPX+Isoflurane groups to evaluate the effect of adenosine A 1 receptor antagonist on isoflurane preconditioning. Dimethyl sulfoxide, the solvent of DPCPX, was administered (1 mL·kg -1 ) 15 min before isoflurane exposure in the Vehicle+Isoflurane group. Neurological deficit scores and brain infarct volumes were evaluated 24 hr after reperfusion. Results: Animals in the Isoflurane and Vehicle+Isoflurane groups developed lower neurological deficit scores and smaller brain infarct volumes than the Control group (P < 0.01). Animals in the DPCPX+Isoflurane group developed higher neurological deficit scores and larger brain infarct volumes than the Isoflurane and Vehicle+Isoflurane groups (P < 0.01). Conclusion:The present study demonstrates that preconditioning with isoflurane reduces focal cerebral ischemic injury in rats, and the adenosine A 1 receptor antagonist (DPCPX) attenuates the neuroprotection induced by isoflurane preconditioning. Objectif

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“…(i) HF þ AF model: male hemizygous cardiac-specific Mst1 Tg mice (C57BL/6, driven by the a myosin heavy chain promoter) 21 were bred with female hemizygous cardiac-specific dnPI3K mice (FVB/N, driven by the a myosin heavy chain promoter) 22 (Mst1, dnPI3K, IGF1R, HSP70) are hemizygous, and all mice were on the same mixed genetic background for any particular cohort. For (i), (ii), (iv) and (v) littermate controls were used.…”

Section: Generation Of Genetic Mouse Modelsmentioning

confidence: 99%

“…We previously described a transgenic (Tg) mouse model with a failing heart, which is susceptible to AF (referred to here as HF þ AF model) 20 . In brief, the model was generated by breeding a cardiac-specific Tg mouse with a failing heart because of dilated cardiomyopathy (DCM, induced with increased activity of mammalian sterile 20-like kinase 1, Mst1; a kinase activated by clinically important pathologic insults such as ischaemia/ reperfusion 21 ) with a cardiac-specific Tg mouse with reduced phosphoinositide 3-kinase (PI3K; because of expression of a dominant negative PI3K (dnPI3K) mutant 22 ). Risk factors for HF and AF, including ageing, obesity and diabetes, have been associated with insulin resistance that can lead to depressed/ defective PI3K signalling [23][24][25] , and PI3K activity was also depressed in atrial tissue from patients with AF 20 .…”

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confidence: 99%

The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice

et al. 2014

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Heart failure (HF) and atrial fibrillation (AF) share common risk factors, frequently coexist and are associated with high mortality. Treatment of HF with AF represents a major unmet need. Here we show that a small molecule, BGP-15, improves cardiac function and reduces arrhythmic episodes in two independent mouse models, which progressively develop HF and AF. In these models, BGP-15 treatment is associated with increased phosphorylation of the insulin-like growth factor 1 receptor (IGF1R), which is depressed in atrial tissue samples from patients with AF. Cardiac-specific IGF1R transgenic overexpression in mice with HF and AF recapitulates the protection observed with BGP-15. We further demonstrate that BGP-15 and IGF1R can provide protection independent of phosphoinositide 3-kinase-Akt and heat-shock protein 70; signalling mediators often defective in the aged and diseased heart. As BGP-15 is safe and well tolerated in humans, this study uncovers a potential therapeutic approach for HF and AF.

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Activation of Mst1 causes dilated cardiomyopathy by stimulating apoptosis without compensatory ventricular myocyte hypertrophy

Cited by 254 publications

References 49 publications

MST1 coordinately regulates autophagy and apoptosis in diabetic cardiomyopathy in mice

MST1 coordinately regulates autophagy and apoptosis in diabetic cardiomyopathy in mice

Neuroanesthesia and Intensive Care Isoflurane tolerance against focal cerebral ischemia is attenuated by adenosine A1 receptor antagonists

The small-molecule BGP-15 protects against heart failure and atrial fibrillation in mice

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