Vascular Smooth Muscle Cell Plasticity and Autophagy in Dissecting Aortic Aneurysms

Clément, Marc; Chappell, Joel; Raffort, Juliette; Lareyre, Fabien; Vandestienne, Marie; Taylor, A.; Finigan, Alison; Harrison, James R.; Bennett, Martin R.; Bruneval, Patrick; Taleb, Soraya; Jørgensen, Helle F.; Mallat, Ziad

doi:10.1161/atvbaha.118.311727

Cited by 132 publications

(125 citation statements)

References 32 publications

(48 reference statements)

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“…For example, our recently published results demonstrated that EZH2 loss of function facilitates autophagic death of VSMCs to aggravate aortic dissection, and we found that LC3, a hall mark of autophagy, is upregulated in the aortic samples of human aortic dissection patients [8]. Importantly, another two independent research groups also verified this result [40,41]. In the present study, we demonstrated that EHMT2 inhibits autophagic death of VSMCs by directly regulating SQSTM1 and BECN1 expression.…”

Section: Discussionsupporting

confidence: 83%

“…Given that VSMCs is indispensable for aorta, and VSMCs death contributes to a variety of vascular diseases (e.g., aortic dissection, aortic aneurysm and atherosclerosis), investigate and elucidate the mechanisms that regulates VSMCs death is urgently needed [39,40]. Autophagy is a "housekeeping" subcellular process that is important in maintaining normal cellular homeostasis and energy balance.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…One of the main responses to hypertension is the cellular proliferation of the intima-media cells, mainly VSMC, with a consequent thickening of the arterial wall [42][43][44][45] . Interestingly, it has been shown that in patients with AD, the thickness of the intima-media layer is reduced compared to control subjects 14,46 and that VSMC proliferation capacity is involved in the pathogenesis of aortic aneurysms and AD 46,47 .…”

Section: Dbc1 Ko Mice Show Decreased Collagen Deposition and Impairedmentioning

confidence: 99%

“…This was evidenced by a decreased rate of BrdU incorporation into DNA and paralleled by a failure to increase the thickness of tunica-media in response to hypertension. Several reports have shown that VSMC proliferation capacity is compromised in AD 14,46,47 and that failure of VSMC could be a cause for aortic wall weakening and aneurysm formation. Recently, we showed that deletion of DBC1 delays cell proliferation in previously quiescent cells, both in vitro and in vivo during liver regeneration 48 .…”

Section: Absence Of Dbc1 Impairs Vascular Cell Proliferation Responsementioning

confidence: 99%

The protein Deleted in Breast Cancer-1 (DBC1) regulates vascular response and formation of aortic dissection during Angiotensin II infusion

Colman

Caggiani

Leyva

et al. 2020

Sci Rep

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Cardiovascular diseases are among the main causes of morbimortality in the adult population. Among them, hypertension is a leading cause for stroke, heart disease and kidney failure. Also, as a result of arterial wall weakness, hypertension can lead to the development of dissecting aortic aneurysms, a rare but often fatal condition if not readily treated. In this work, we investigated the role of DBC1 in the regulation of vascular function in an ANGII-induced hypertension mouse model. We found that WT and DBC1 KO mice developed hypertension in response to ANGII infusion. However, DBC1 KO mice showed increased susceptibility to develop aortic dissections. The effect was accompanied by upregulation of vascular remodeling factors, including MMP9 and also VEGF. Consistent with this, we found decreased collagen deposition and elastic fiber fragmentation, suggesting that increased expression of MMPs in DBC1 KO mice weakens the arterial wall, promoting the formation of aortic dissections during treatment with ANGII. Finally, DBC1 KO mice had reduced cell proliferation in the intima-media layer in response to ANGII, paralleled with an impairment to increase wall thickness in response to hypertension. Furthermore, VSMC purified from DBC1 KO mice showed impaired capacity to leave quiescence, confirming the in vivo results. Altogether, our results show for the first time that DBC1 regulates vascular response and function during hypertension and protects against vascular injury. This work also brings novel insights into the molecular mechanisms of the development of aortic dissections.General reagents and antibodies. All general reagents and chemicals were purchased from Sigma-Aldrich, including angiotensin II (ANGII, A9525), unless otherwise specified. Lipofectamine RNAiMax, Bradford protein assay reagent, Trizol and SuperScript II RT were bought from Invitrogen. SiRNAs oligos were purchased from Ambion (Negative Control 4390843; HDAC3 4390771) or Invitrogen (DBC1 MSS211964 and SIRT1 MSS234959). Antibodies were purchased from Bethyl (anti DBC1, 434 A), Abcam (anti tubulin 7291, anti BrdU 6326, anti KI67 16667), or Cell Signaling (anti Cyclin D1 9262, anti PCNA 92552). DNase I and Fast SYBR Green were purchased from Roche.Animal handling and experiments. All mice used in this study were maintained at the Institut Pasteur de Montevideo Animal facility (UATE). The experimental protocol was approved by the Institutional Animal Care and Use Committee of the Institut Pasteur de Montevideo (CEUA, Protocol number 014-14). All the studies described were performed according to the methods approved in the protocol and following all international guidelines and legal regulations. WT and whole-body DBC1 KO mice were in a C57BL6/J pure background. DBC1 KO mice were backcrossed into C57BL/6 J for more than 10 generations in order to ensure genetic purity. Mice received standard chow and water ad libitum. Scientific RepoRtS |(2020) 10:6772 | https://doi.negative control, DBC1, HDAC3 and SIRT1 using 25 pmol Lipofectamine RNAiMax. After 24 h...

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HRD1 reduction promotes cholesterol-induced vascular smooth muscle cell phenotypic change via endoplasmic reticulum stress

Wang,

Ren,

et al. 2023

Mol Cell Biochem

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Aims: Phenotypic change of vascular smooth muscle cells (VSMCs) contributes a lot in obesity induced vascular pathological remodeling. The endoplasmic reticulum (ER) is critical for maintaining VSMC function, but the accumulation of misfolded proteins in the ER impairs cell function. As the major ER protein quality control responsible for clearing misfolded proteins, ER-associated degradation (ERAD) whose key member is HRD1 plays vital role in lipid metabolism, but its function in VSMC phenotypic change remains poorly understood.Main methods: The level of HRD1 expression was analyzed in aortic tissues of mice fed with a high-fat diet (HFD). The HE and EVG (VERHOEFF'S VAN GIESON) staining were used to demonstrate vascular pathological changes. Cripr and transcriptomic analysis were applied in in vitro studies to explore the cellular mechanism. Key ndings: Data showed a signi cant reduction of HRD1 in aortic tissues of mice under HFD feeding. VSMC phenotypic change and HRD1 downregulation were detected by cholesterol treatment.Transcriptomic and further analysis of HRD1-KO VSMCs showed that HRD1 de ciency increased the expression of genes related with ER stress, proliferation, and migration, but decreased the VSMC contractile-related genes. HRD1 de ciency in VSMCs also exacerbated the proliferation, migration, and ROS production induced by cholesterol, which promoted the VSMC phenotypic change process.Signi cance: Our results proved that HRD1 plays an essential role in the contractile homeostasis of VSMCs by negatively regulating ER stress. Thus, HRD1 may have the potential to be a therapeutic target in lipid metabolic disorders induced vascular remodeling caused by VSMC phenotypic change. HighlightsWe proved HRD1 KO exacerbated the proliferation, migration, and ROS production induced by cholesterol, promoted the VSMCs transfer from a contractile phenotype to a synthetic phenotype, our study provided a new target in treating the vascular pathological remodeling caused by VSMC phenotypic change.University, as well as the Animal Laboratory Administration Center and Ethics Committee of the Sun Yat-Sen University, the third a liated hospital. Male C57Bl6/J mice were purchased from the Guangdong Medical Laboratory Animal center. The persistent ID is SYSU-IACUC-2022-001869. All mice were maintained in a SPF environment with controlled humidity and temperature (22 ± 2°C) under a 12 h:12 h light/dark cycle and received water and a chow diet (CD) ad libitum. At 2 months of age, the mice were divided to receive CD (3.86 kcal/g), or HFD (a very high fat, 60% calories from fat; 5.55 kcal/g diet) for 4 months. Manipulations of Cultured VSMCsHuman primary VSMCs were purchased from Guangzhou BIOSPECIES Company (batch number 20220704), shown in Table SI, cultured in DMEM containing 10% fetal bovine serum and antibiotics (1% ER: endoplasmic reticulum VSMC: vascular smooth muscle cell ERAD: endoplasmic reticulum-associated degradation UPR: unfolded protein response

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Vascular Smooth Muscle Cell Plasticity and Autophagy in Dissecting Aortic Aneurysms

Abstract: Supplemental Digital Content is available in the text.

Cited by 132 publications

References 32 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

The protein Deleted in Breast Cancer-1 (DBC1) regulates vascular response and formation of aortic dissection during Angiotensin II infusion

HRD1 reduction promotes cholesterol-induced vascular smooth muscle cell phenotypic change via endoplasmic reticulum stress

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