Cardiac‐specific Mst1 deficiency inhibits <scp>ROS</scp>‐mediated <scp>JNK</scp> signalling to alleviate Ang <scp>II</scp>‐induced cardiomyocyte apoptosis

Cheng, Zheng; Zhang, Mingming; Hu, Jianqiang; Lin, Jie; Feng, Xinyu; Wang, Shanjie; Wang, Tingting; Gao, Erhe; Wang, Haichang; Sun, Dongdong

doi:10.1111/jcmm.13958

Cited by 27 publications

(14 citation statements)

References 35 publications

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“…An elevated level of Ang II, a vessel contractor molecule, in the heart is associated with an increased rate of myocardial apoptosis [ 26 , 27 ]. Many studies have demonstrated that inhibition of apoptosis is cardioprotective and can prevent the development of HF [ 9 ]. Pharmacological intervention is one of the several strategies used to reduce apoptosis during cardiac injury [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…Mitochondrial reactive oxygen species (mtROS) generation during cellular aerobic respiration and metabolism is implicated in cardiovascular pathologies [ 8 ]. The production of large quantities of mtROS via Ang II activation can trigger the destruction of intracellular proteins, organelles, and DNA [ 9 ]. Attenuating mtROS levels and thereby reducing oxidative stress can alleviate cardiomyocyte apoptosis.…”

Section: Introductionmentioning

confidence: 99%

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Activation of the M3AChR and Notch1/HSF1 Signaling Pathway by Choline Alleviates Angiotensin II‐Induced Cardiomyocyte Apoptosis

Xu¹,

Xue³

et al. 2021

Oxidative Medicine and Cellular Longevity

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Angiotensin II- (Ang II-) induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure. Choline exerts cardioprotective effects; however, its effects on Ang II-induced cardiomyocyte apoptosis are unclear. In this study, the role and underlying mechanism of choline in regulating Ang II-induced cardiomyocyte apoptosis were investigated using a model of cardiomyocyte apoptosis, which was induced by exposing neonatal rat cardiomyocytes to Ang II (10−6 M, 48 h). Choline promoted heat shock transcription factor 1 (HSF1) nuclear translocation and the intracellular domain of Notch1 (NICD) expression. Consequently, choline attenuated Ang II-induced increases in mitochondrial reactive oxygen species (mtROS) and promotion of proapoptotic protein release from mitochondria, including cytochrome c, Omi/high-temperature requirement protein A2, and second mitochondrial activator of caspases/direct inhibitor of apoptosis-binding protein with low P. The reversion of these events attenuated Ang II-induced increases in cardiomyocyte size and numbers of terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-positive cells, presumably via type 3 muscarinic acetylcholine receptor (M3AChR). Indeed, downregulation of M3AChR or Notch1 blocked choline-mediated upregulation of NICD and nuclear HSF1 expression, as well as inhibited mitochondrial apoptosis pathway and cardiomyocyte apoptosis, indicating that M3AChR and Notch1/HSF1 activation confer the protective effects of choline. In vivo studies were performed in parallel, in which rats were infused with Ang II for 4 weeks to induce cardiac apoptosis. The results showed that choline alleviated cardiac remodeling and apoptosis of Ang II-infused rats in a manner related to activation of the Notch1/HSF1 pathway, consistent with the in vitro findings. Taken together, our results reveal that choline impedes oxidative damage and cardiomyocyte apoptosis by activating M3AChR and Notch1/HSF1 antioxidant signaling, and suggest a novel role for the Notch1/HSF1 signaling pathway in the modulation of cardiomyocyte apoptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activation of the M3AChR and Notch1/HSF1 Signaling Pathway by Choline Alleviates Angiotensin II‐Induced Cardiomyocyte Apoptosis

Xu¹,

Xue³

et al. 2021

Oxidative Medicine and Cellular Longevity

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“…At the molecular level, Sirt3 inactivated the Mst1-JNK pathway and thus suppressed the expression of SRV2, a novel mediator of mitochondrial fission. The Mst1-JNK axis is known to control mitochondrial fission in liver cancer [43], hyperglycemia-induced vascular dysfunction [44], thyroid carcinoma [45], breast cancer [46], acute cardiac stress [47], and colorectal cancer [48]. In addition, SRV2 induces mitochondrial fission by promoting F-actin polymerization [49, 50].…”

Section: Discussionmentioning

confidence: 99%

Sirtuin 3 attenuates neuroinflammation-induced apoptosis in BV-2 microglia

Zhou

Jiang

2019

Aging

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In this study, we explored the upstream regulatory mechanisms underlying inflammation-induced mitochondrial dysfunction in microglial BV-2 cells. Our results demonstrate that Sirtuin 3 (Sirt3) expression was downregulated in response to LPS-induced neuroinflammation. In addition, overexpression of Sirt3 attenuated LPS-induced BV-2 cell death. Functional studies illustrated that Sirt3 overexpression promoted normal mitochondrial function and inhibited mitochondria-dependent apoptosis in LPS-treated BV-2 cells. At the molecular level, suppressor of ras val-2 (SRV2) promoted LPS-mediated mitochondrial damage by inducing mitochondrial fission. Sirt3 overexpression, which suppressed the transcription of SRV2 and thus suppressed mitochondrial fission, played an anti-apoptotic role in LPS-treated BV-2 cells. Furthermore, Sirt3 inhibited SRV2 expression via the Mst1-JNK pathway, and re-activation of this pathway abolished the protective effects of Sirt3 on mitochondrial damage and apoptosis. Taken together, our results indicate that Sirt3-induced, Mst1-JNK-SRV2 signaling pathway-dependent inhibition of mitochondrial fission protected against neuroinflammation-mediated cell damage in BV-2 microglia. Sirt3 might therefore be an effective treatment for neuroinflammation.

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“…Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) stainings were used to detect primary cardiomyocyte apoptosis. TUNEL staining was performed with fluorescein‐dUTP (In Situ Cell Death Detection Kit; Roche Diagnostics) for apoptotic cell nuclei and DAPI (Sigma‐Aldrich) stained all cell nuclei (Cheng et al, ). The apoptotic rate was calculated as the proportion of the number of apoptotic myocytes to the total myocytes from a total of 10 fields per group.…”

Section: Methodsmentioning

confidence: 99%

Lin28a protects against diabetic cardiomyopathy through Mst1 inhibition

You

Cheng

et al. 2019

Journal Cellular Physiology

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Lin28a has been found to enhance glucose uptake and insulin sensitivity. Lin28a alleviates cardiac dysfunction under various pathological conditions. However, the effects and underlying mechanisms of Lin28a on diabetic cardiomyopathy (DCM) are not well-understood. The aim of this study was to determine whether Lin28a protects against DCM and the potential mechanisms. Two to three days old mouse neonatal primary cardiomyocytes were randomized for treatment with adenoviruses harboring Lin28a and mammalian sterile 20-like kinase 1 (Mst1) short hairpin RNA, 48 hr before culturing in normal or high glucose medium. Cardiomyocyte apoptosis, autophagy, mitochondrial morphology, adenosine triphosphate content, and cytokine levels in the high glucose or normal conditions were observed between all groups. Either Lin28a overexpression or Mst1 knockdown alleviated mitochondrial ultrastructure impairment, decreased cytokine levels, inhibited apoptosis, and enhanced autophagy in primary neonatal mouse cardiomyocytes treated with high glucose. Importantly, the protective effects of Lin28a and Mst1 disappeared after treatment with 3-methyladenine, an autophagy inhibitor. Interestingly, in Mst1 knockdown cardiomyocytes, Lin28a overexpression failed to further enhance autophagy and alleviate high glucose-induced cardiomyocyte injury, which implies the protective roles of Lin28a counteracting high glucose-induced cardiomyocyte injury are dependent on Mst1 inhibition. Furthermore, co-immunoprecipitation and immunofluorescence double staining suggested that there were no direct interactions between Mst1 and Lin28a. Lin28a increased the expression of Akt, which inhibited the activation of Mst1-mediated apoptotic pathways. K E Y W O R D S apoptosis, autophagy, diabetic cardiomyopathy, Lin28a, Mst1 SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section. How to cite this article: You P, Cheng Z, He X, et al. Lin28a protects against diabetic cardiomyopathy through Mst1 inhibition. J Cell Physiol. 2020;235:4455-4465.

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Cardiac‐specific Mst1 deficiency inhibits ROS‐mediated JNK signalling to alleviate Ang II‐induced cardiomyocyte apoptosis

Cited by 27 publications

References 35 publications

Activation of the M3AChR and Notch1/HSF1 Signaling Pathway by Choline Alleviates Angiotensin II‐Induced Cardiomyocyte Apoptosis

Activation of the M3AChR and Notch1/HSF1 Signaling Pathway by Choline Alleviates Angiotensin II‐Induced Cardiomyocyte Apoptosis

Sirtuin 3 attenuates neuroinflammation-induced apoptosis in BV-2 microglia

Lin28a protects against diabetic cardiomyopathy through Mst1 inhibition

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