Defective autophagy in vascular smooth muscle cells enhances cell death and atherosclerosis

Osonoi, Yusuke; Mita, Tomoya; Azuma, Kosuke; Nakajima, Kénichi; Masuyama, Atsushi; Goto, Hiromasa; Nishida, Yuya; Miyatsuka, Takeshi; Fujitani, Yoshio; Koike, Masato; Mitsumata, Masako

doi:10.1080/15548627.2018.1501132

Cited by 112 publications

(77 citation statements)

References 43 publications

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“…Studies have shown that autophagy inhibits the progression of AS, whereas defective autophagy in vascular wall cells enhances its progression. 33,34 In this study, we found that metformin and si-TUG1 reduced the proliferation and migration of HUVECs. There is a strong connection between autophagy and vascular wall cell proliferation/migration in AS.…”

Section: Discussionsupporting

confidence: 49%

Metformin Activates the AMPK-mTOR Pathway by Modulating lncRNA TUG1 to Induce Autophagy and Inhibit Atherosclerosis

You¹,

Long²,

Song³

et al. 2020

DDDT

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Background: Metformin has been shown to inhibit the proliferation and migration of vascular wall cells. However, the mechanism through which metformin acts on atherosclerosis (AS) via the long non-coding RNA taurine up-regulated gene 1 (lncRNA TUG1) is still unknown. Thus, this research investigated the effect of metformin and lncRNA TUG1 on AS. Methods: First, qRT-PCR was used to detect the expression of lncRNA TUG1 in patients with coronary heart disease (CHD). Then, the correlation between metformin and TUG1 expression in vitro and their effects on proliferation, migration, and autophagy in vascular wall cells were examined. Furthermore, in vivo experiments were performed to verify the anti-AS effect of metformin and TUG1 to provide a new strategy for the prevention and treatment of AS. Results: qRT-PCR results suggested that lncRNA TUG1 expression was robustly upregulated in patients with CHD. In vitro experiments indicated that after metformin administration, the expression of lncRNA TUG1 decreased in a time-dependent manner. Metformin and TUG1 knockdown via small interfering RNA both inhibited proliferation and migration while promoted autophagy via the AMPK/mTOR pathway in vascular wall cells. In vivo experiments with a rat AS model further demonstrated that metformin and sh-TUG1 could inhibit the progression of AS. Conclusion: Taken together, our data demonstrate that metformin might function to prevent AS by activating the AMPK/mTOR pathway via lncRNA TUG1.

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Section: Discussionsupporting

confidence: 49%

Metformin Activates the AMPK-mTOR Pathway by Modulating lncRNA TUG1 to Induce Autophagy and Inhibit Atherosclerosis

You¹,

Long²,

Song³

et al. 2020

DDDT

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“…In the present study, we demonstrated that EHMT2 inhibits autophagic death of VSMCs by directly regulating SQSTM1 and BECN1 expression. However, some other research group hold the opinion that autophagy is a protective process, because VSMC-specific deletion of autophagy related genes (e.g., ATG5 and ATG7) usually impaired VSMC autophagy and increased cell death to affect atherosclerosis or dissecting aortic aneurysms [40,42,43]. These studies further indicated that autophagy is a double-edged sword in VSMCs.…”

Section: Discussionmentioning

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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“…The atherosclerotic process is enhanced by diabetes, smoking, hypertension, hyperlipidemia, abdominal obesity (metabolic syndrome), kidney insufficiency, persistent proteinuria and so on [34] . In early atherosclerosis, lipoproteins are retained and modified in the vessel wall, resulting in inflammatory responses in the surrounding cells.…”

Section: Discussionmentioning

confidence: 99%

Carotid artery ultrasound for evaluating the degree of stenosis and plaque composition in patients with coronary heart disease

Zhu¹,

You²,

Xu³

et al. 2019

Preprint

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Background: Early screening, diagnosis, risk assessment, and intervention of intima-media thickness (IMT) and carotid plaques is critical for assessing the risk of coronary heart disease (CHD). The current study aimed to assess carotid IMT and atherosclerotic plaque composition in patients with CHD by carotid artery ultrasound and to determine the associations of various factors with CHD. Methods: 480 patients with suspected CHD underwent a duplex ultrasound of the carotid arteries and coronary angiography or coronary CT. Then, the patients were investigated and evaluated to identify both personal and medical histories of clinical evaluations, and divided into the CHD (n=325) and control (n=155) groups based on clinical symptoms and vessel lesions. Associations of clinical characteristics with ischemic lesions determined by coronary angiography or CT were examined. Screening by B-mode carotid artery ultrasonography was performed the morning after admission prior to any treatment, coronary angiography or CT. Results: Cardiac diagnostic testing was performed in 134 subjects by CT coronary angiography, while the remaining 346 patients underwent coronary angiography. Carotid plaques were mainly distributed in the common carotid artery, with a significant difference between the CHD and control groups. Plaque incidence (80%) and IMT thickness (0.84±0.21) were significantly higher in the CHD group compared with control patients (P=8.92e-12 and P=0.012 respectively). The factors significantly associated with CHD were selected into the multivariate regression model. Male subject (OR=1.569, 95%CI 1.004-2.453; P=0.048) and plaque level (OR=0.457, 95%CI 0.210-0.993; P=0.048) were significant for CHD occurrence. The carotid plaque performed significantly better than IMT and the Framingham CHD risk score for predicting CHD risk (DeLong's correlated AUC test P=5.84e-4 and P=2.52e-5, respectively). Conclusions: The present study demonstrated that carotid artery ultrasound could be an effective method for early detection of atherosclerosis, which would help prevent CHD in asymptomatic patients with advanced atherosclerosis of the carotid artery. Incorporating carotid artery ultrasound plaque composition into screen practice may perform significantly better than the Framingham CHD risk factors for predicting CHD risk.

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Defective autophagy in vascular smooth muscle cells enhances cell death and atherosclerosis

Cited by 112 publications

References 43 publications

<p>Metformin Activates the AMPK-mTOR Pathway by Modulating lncRNA <em>TUG1</em> to Induce Autophagy and Inhibit Atherosclerosis</p>

<p>Metformin Activates the AMPK-mTOR Pathway by Modulating lncRNA <em>TUG1</em> to Induce Autophagy and Inhibit Atherosclerosis</p>

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

Carotid artery ultrasound for evaluating the degree of stenosis and plaque composition in patients with coronary heart disease

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