The Histone Methyltransferase Mixed Lineage Leukemia (MLL) 3 May Play a Potential Role in Clinical Dilated Cardiomyopathy

Jiang, Ding-Sheng; Yi, Xin; Li, Rui; Su, Yue; Wang, Jing; Chen, Min-Lai; Liu, Ligang; Hu, Min; Cheng, Can; Zheng, Ping; Zhu, Xiashi; Wei, Xiang

doi:10.2119/molmed.2017.00012

Cited by 37 publications

(30 citation statements)

References 46 publications

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“…Western blotting was performed as previously reported. [22][23][24] The antibodies used in this study including LC3II/I (#12741), ATG5 (#12994), ATG7 (#8558), ATG12 (#4180), ATG16L (#8089), BECN1 (#3495), Desmin (#5332), and Vimentin (#5741) were obtained from Cell Signaling Technology. Antibodies against histone H3 (ab1791), H3K9me1 (ab9045), H3K9me2 (ab1220), EHMT2 (ab185050), α-SMA (ab7817), SM22α (ab14106), and SQSTM1 (ab56416) were purchased from Abcam.…”

Section: Western Blot Analysismentioning

confidence: 99%

EHMT2/G9a Inhibits Aortic Smooth Muscle Cell Death by Suppressing Autophagy Activation

Chen¹,

Hu²,

Huo³

et al. 2020

Int. J. Biol. Sci.

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Although EHMT2 (also known as G9a) plays a critical role in several kinds of cancers and cardiac remodeling, its function in vascular smooth muscle cells (VSMCs) remains unknown. In the present study, we revealed a novel function of EHMT2 in regulating autophagic cell death (ACD) of VSMC. Inhibition of EHMT2 by BIX01294 or knockdown of EHMT2 resulted in reduced VSMC numbers which were independent of proliferation and apoptosis. Interestingly, EHMT2 protein levels were significantly decreased in VSMCs treated with autophagic inducers. Moreover, more autophagic vacuoles and accumulated LC3II were detected in VSMCs treated with BIX01294 or lenti-shEHMT2 than their counterparts. Furthermore, we found that EHMT2 inhibited the ACD of VSMCs by suppressing autophagosome formation. Mechanistically, the pro-autophagic effect elicited by EHMT2 inhibition was associated with SQSTM1 and BECN1 overexpression. Moreover, these detrimental effects were largely nullified by SQSTM1 or BECN1 knockdown. More importantly, similar results were observed in primary human aortic VSMCs. Overall, these findings suggest that EHMT2 functions as a crucial negative regulator of ACD via decreasing SQSTM1 or BECN1 expression and that EHMT2 could be a potent therapeutic target for cardiovascular diseases (e.g., aortic dissection).

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Section: Western Blot Analysismentioning

confidence: 99%

EHMT2/G9a Inhibits Aortic Smooth Muscle Cell Death by Suppressing Autophagy Activation

Chen¹,

Hu²,

Huo³

et al. 2020

Int. J. Biol. Sci.

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“…Protein methylation usually occurs on lysine or arginine, and both histones and nonhistone proteins can be methylated [ 104 – 106 ]. A plethora of studies have demonstrated that protein methylation plays an important role in cell survival/death and diseases [ 104 , 107 – 109 ], but the research on their roles in ferroptosis is in its infancy. For example, lysine demethylase 3B (KDM3B), a histone H3K9 demethylase, inhibits erastin-induced ferroptosis by cooperating with the transcription factor activating transcription factor 4 (ATF4) to upregulate SLC7A11 expression [ 110 ] ( Figure 4 ).…”

Section: Posttranslational Modifications (Ptms) In Ferroptosismentioning

confidence: 99%

Posttranslational Modifications in Ferroptosis

Wei

Zhu

et al. 2020

Oxidative Medicine and Cellular Longevity

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130

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Ferroptosis was first coined in 2012 to describe the form of regulated cell death (RCD) characterized by iron-dependent lipid peroxidation. To date, ferroptosis has been implicated in many diseases, such as carcinogenesis, degenerative diseases (e.g., Huntington’s, Alzheimer’s, and Parkinson’s diseases), ischemia-reperfusion injury, and cardiovascular diseases. Previous studies have identified numerous targets involved in ferroptosis; for example, acyl-CoA synthetase long-chain family member 4 (ACSL4) and p53 induce while glutathione peroxidase 4 (GPX4) and apoptosis-inducing factor mitochondria-associated 2 (AIFM2, also known as FSP1) inhibit ferroptosis. At least three major pathways (the glutathione-GPX4, FSP1-coenzyme Q10 (CoQ10), and GTP cyclohydrolase-1- (GCH1-) tetrahydrobiopterin (BH4) pathways) have been identified to participate in ferroptosis regulation. Recent advances have also highlighted the crucial roles of posttranslational modifications (PTMs) of proteins in ferroptosis. Here, we summarize the recently discovered knowledge regarding the mechanisms underlying ferroptosis, particularly the roles of PTMs in ferroptosis regulation.

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“…Histology and immunohistochemistry staining were performed as previously described (16). Human and mouse aortic samples were fixed in 4% paraformaldehyde and embedded in paraffin, and then 5-µm-thick serial sections were stained with hematoxylin-eosin (H&E) for morphological examination.…”

Section: Histology and Immunohistochemistry Stainingmentioning

confidence: 99%

Downregulation of Filamin a Expression in the Aorta Is Correlated With Aortic Dissection

Chen

Wei

Zhang

et al. 2021

Front. Cardiovasc. Med.

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Filamins (FLNs) are actin cross-linking proteins, and as scaffolding proteins, FLNs are closely associated with the stabilization of the cytoskeleton. Nevertheless, the biological importance of FLNs in aortic dissection (AD) has not been well-elucidated. In this study, we first reanalyzed datasets downloaded from the Gene Expression Omnibus (GEO) database, and we found that in addition to the extracellular matrix, the actin cytoskeleton is a key structure associated with AD. Given that FLNs are involved in remodeling the cytoskeleton to affect cellular functions, we measured their expression levels in the aortas of patients with Stanford type A AD (TAAD). Our results showed that the mRNA and protein levels of FLNA were consistently decreased in dissected aortas of both humans and mice, while the FLNB protein level was upregulated despite decreased FLNB mRNA levels, and comparable expression levels of FLNC were observed between groups. Furthermore, the immunohistochemistry results demonstrated that FLNA was highly expressed in smooth muscle cells (SMCs) of aorta in non-AD samples, and downregulated in the medial layer of the dissected aortas of humans and mice. Moreover, we revealed that FOS and JUN, forming a dimeric transcription factor called AP-1 (activating protein-1), were positively correlated with the expression of FLNA in aorta. Either overexpression of FOS or JUN alone, or overexpression of FOS and JUN together, facilitated the expression of FLNA in primary cultured human aortic SMCs. In the present study, we not only detected the expression pattern of FLNs in aortas of humans and mice with or without AD, but we also found that the expression of FLNA in the AD samples was significantly reduced and that AP-1 might regulate the expression of FLNA. Our findings will contribute to the elucidation of the pathological mechanisms of AD and provide potential therapeutic targets for AD.

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The Histone Methyltransferase Mixed Lineage Leukemia (MLL) 3 May Play a Potential Role in Clinical Dilated Cardiomyopathy

Cited by 37 publications

References 46 publications

EHMT2/G9a Inhibits Aortic Smooth Muscle Cell Death by Suppressing Autophagy Activation

EHMT2/G9a Inhibits Aortic Smooth Muscle Cell Death by Suppressing Autophagy Activation

Posttranslational Modifications in Ferroptosis

Downregulation of Filamin a Expression in the Aorta Is Correlated With Aortic Dissection

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