Mst1 participates in the atherosclerosis progression through macrophage autophagy inhibition and macrophage apoptosis enhancement

Wang, Tingting; Zhang, Lei; Hu, Jianqiang; Duan, Yu; Zhang, Mingming; Lin, Jie; Man, Wanrong; Pan, Xietian; Jiang, Zhenhua; Zhang, Guoyong; Gao, Beilei; Wang, Haichang; Sun, Dongdong

doi:10.1016/j.yjmcc.2016.08.002

Cited by 44 publications

(35 citation statements)

References 34 publications

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“…Interestingly, melatonin inhibited Mst1 phosphorylation, upregulated LC3‐II expression as well as decreased the accumulation of p62 and aggresomes. Our recent studies documented that suppressed autophagic flux is a contributing mechanism for Mst1‐mediated cardiovascular pathologies at various pathological settings including diabetes . In the present study, melatonin also enhanced autophagic flux as evidenced by increased LC3‐II/GAPDH ratio and decreased p62 expression in the presence of the lysosomal inhibitor bafilomycin A1.…”

Section: Discussionsupporting

confidence: 73%

Melatonin protects against diabetic cardiomyopathy through Mst1/Sirt3 signaling

Zhang

Lin

Wang

et al. 2017

Journal of Pineal Research

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152

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This study investigated the effects of melatonin on diabetic cardiomyopathy (DCM) and determined the underlying mechanisms. Echocardiography indicated that melatonin notably mitigated the adverse left ventricle remodeling and alleviated cardiac dysfunction in DCM. The mechanisms were attributed to increased autophagy, reduced apoptosis, and alleviated mitochondrial dysfunction. Furthermore, melatonin inhibited Mst1 phosphorylation and promoted Sirt3 expression in DCM. These results indicated that melatonin may exert its effects through Mst1/Sirt3 signaling. To verify this hypothesis, a DCM model using Mst1 transgenic (Mst1 Tg) and Mst1 knockout (Mst1 ) mice was constructed. As expected, melatonin increased autophagy, reduced apoptosis and improved mitochondrial biogenesis in Mst1 Tg mice subjected to DCM injury, while it had no effects on Mst1 mice. In addition, cultured neonatal mouse cardiomyocytes were subjected to simulated diabetes to probe the mechanisms involved. Melatonin administration promoted autophagic flux as demonstrated by elevated LC3-II and lowered p62 expression in the presence of bafilomycin A1. The results suggest that melatonin alleviates cardiac remodeling and dysfunction in DCM by upregulating autophagy, limiting apoptosis, and modulating mitochondrial integrity and biogenesis. The mechanisms are associated with Mst1/Sirt3 signaling.

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Section: Discussionsupporting

confidence: 73%

Melatonin protects against diabetic cardiomyopathy through Mst1/Sirt3 signaling

Zhang

Lin

Wang

et al. 2017

Journal of Pineal Research

Self Cite

152

124

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“…However, the significance of insufficient lipophagy underlying foam cell formation or progression is still not known. On the other hand, in a recent study on the tumor-supressor gene programmed cell death 4 (PDCD4), it was demonstrated that the protein inhibited autophagy in macrophages, and Pdcd4 knockout mice displayed increased atherosclerosis, indicating a link between autophagy and atherogenesis [157]. …”

Section: Introductionmentioning

confidence: 99%

Lipid Droplets in Health and Disease

et al. 2017

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Lipids are essential building blocks synthesized by complex molecular pathways and deposited as lipid droplets (LDs) in cells. LDs are evolutionary conserved organelles found in almost all organisms, from bacteria to mammals. They are composed of a hydrophobic neutral lipid core surrounding by a phospholipid monolayer membrane with various decorating proteins. Degradation of LDs provide metabolic energy for divergent cellular processes such as membrane synthesis and molecular signaling. Lipolysis and autophagy are two main catabolic pathways of LDs, which regulate lipid metabolism and, thereby, closely engaged in many pathological conditons. In this review, we first provide an overview of the current knowledge on the structural properties and the biogenesis of LDs. We further focus on the recent findings of their catabolic mechanism by lipolysis and autophagy as well as their connection ragarding the regulation and function. Moreover, we discuss the relevance of LDs and their catabolism-dependent pathophysiological conditions.

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“…Previous studies have shown that PDCD4 deficiency clearly improved ox-LDL-impaired autophagy efflux, promoted autophagy-mediated lipid breakdown in murine macrophages and thus prevented macrophage conversion into foam cells. 15,16 Here, we detected the efficiency of two shPDCD4 (shPDCD4-1 and shPDCD4-2) by real-time RT-PCR and Western blot analysis. ShPDCD4-1 showed higher efficiency in knocking down of both ( Figure 3A), so we used the shPDCD4-1 for the experiment after.…”

Section: Age-ldl-induced Autophagymentioning

confidence: 99%

“…14 Furthermore, PDCD4 deficiency attenuates oxidized-LDL (ox-LDL) induces foam cell formation and atherosclerosis in mice, which collectively demonstrated the important role of PDCD4 on the regulation of autophagy-dependent cholesterol efflux, foam cell formation, and atherosclerosis. 15,16 The aim of the present study was to investigate the role of PDCD4 involved in AGE-LDL-induced macrophage autophagy and cell apoptosis in macrophage cell line RAW264.7. We report here that the three aforementioned factors, PDCD4, autophagy, and apoptosis, form a unique regulatory streamline that controls cells destiny during AGE-LDLinduced foam cell formation.…”

Section: Introductionmentioning

confidence: 99%

Programmed cell death protein 4 deficiency suppresses foam cell formation by activating autophagy in advanced glycation end‐product low‐density lipoprotein–induced macrophages

Gao

et al. 2018

J of Cellular Biochemistry

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Background Advanced glycation end‐product is a modified form of low‐density lipoprotein (AGE‐LDL) and accelerates atherosclerosis through undefined mechanisms. Programmed cell death protein 4 (PDCD4), a transcriptional regulator, plays an important role in the regulation of autophagy. The aim of the present study was to investigate the role of PDCD4 involved in AGE‐LDL–induced foam cell formation. Methods The characterization of AGE‐LDL was measured by the thiobarbituric assay and agarose gel electrophoresis in vitro. RAW264.7, THP‐1 cell line and primary peritoneal macrophages of mice were transfected with shPDCD4 plasmid AGE‐LDL–induced foam cell formation was stained by Oil Red, and the levels of autophagy and apoptosis were determined by Western blot analysis. Autophagosome was observed with immunofluorescence microscopy. Mitochondrial membrane potential and autophagic flux were assessed by flow cytometry. Results AGE modification resulted in significant reduction of absorbance shown by thiobarbituric assay and augmentation of electrophoresis mobility. Further studies suggest that macrophages exposed AGE‐LDL triggered autophagy in the early stage of foam cell formation. PDCD4 deficiency enhanced lipoautophagy but inhibited apoptosis and mitochondria dysfunction. Previous studies have been reported that autophagy is an adaptive response might prevent lesional macrophage apoptosis. In our study, we found PDCD4 deficiency attenuated apoptosis and AGE‐LDL–induced foam cell formation relied on increased autophagy. Conclusion Our data revealed that PDCD4 deficiency can facilitate autophagy and benefit for AGE‐LDL–induced foam cell formation.

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Mst1 participates in the atherosclerosis progression through macrophage autophagy inhibition and macrophage apoptosis enhancement

Cited by 44 publications

References 34 publications

Melatonin protects against diabetic cardiomyopathy through Mst1/Sirt3 signaling

Melatonin protects against diabetic cardiomyopathy through Mst1/Sirt3 signaling

Lipid Droplets in Health and Disease

Programmed cell death protein 4 deficiency suppresses foam cell formation by activating autophagy in advanced glycation end‐product low‐density lipoprotein–induced macrophages

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