scholarly journals XIST knockdown suppresses vascular smooth muscle cell proliferation and induces apoptosis by regulating miR-1264/WNT5A/β-catenin signaling in aneurysm

2021 ◽  
Author(s):  
Liang Zou ◽  
Lei Chen ◽  
Peng-fei Xia ◽  
Yan-yan Hou
Keyword(s):  
Cell Proliferation ◽  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Vascular Smooth Muscle ◽  
Molecular Mechanisms ◽  
Xist Expression ◽  
Wnt5a Expression ◽  
Abdominal Aortic ◽  
Lncrna Xist

LncRNAs have been ascertained as vital modulators in abdominal aortic aneurysm (AAA) development. In this research, the function and molecular mechanisms of the lncRNA XIST in the evolution of vascular smooth muscle cells (VSMCs) were assessed. Results showed that XIST expression was increased but miR-1264 expression level was reduced in the serum of AAA patients. XIST depletion impeded HA-VSMCs’ ability to proliferate and stimulate apoptosis, while repressing miR-1264 expression through an unmediated interaction. Additionally, the influence of XIST knockdown on apoptosis and proliferation could be rescued by a miR-1264 inhibitor. Subsequent molecular investigations indicated that WNT5A was miR-1264's target, and XIST functioned as a ceRNA of miR-1264 to raise WNT5A expression. Further, a miR-1264 inhibitor stimulated the proliferation and suppressed the apoptosis of HA-VSMCs through the activation of WNT/β-catenin signaling. Taken together, XIST impeded the apoptosis and stimulated the proliferation of HA-VSMCs via the WNT/β-catenin signaling pathway through miR-1264, demonstrating XIST's underlying role in AAA.

scholarly journals SM22α Loss Contributes to Apoptosis of Vascular Smooth Muscle Cells via Macrophage-Derived circRasGEF1B

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Pin Lv ◽  
Ya-Juan Yin ◽  
Peng Kong ◽  
Li Cao ◽  
Hao Xi ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Vascular Smooth Muscle ◽  
Inflammatory Cell ◽  
Activated Macrophages ◽  
Abdominal Aortic ◽  
Specific Manner ◽  
Higher Sensitivity

Vascular smooth muscle cell (VSMC) apoptosis is a major defining feature of abdominal aortic aneurysm (AAA) and mainly caused by inflammatory cell infiltration. Smooth muscle (SM) 22α prevents AAA formation through suppressing NF-κB activation. However, the role of SM22α in VSMC apoptosis is controversial. Here, we identified that SM22α loss contributed to apoptosis of VSMCs via activation of macrophages. Firstly, deficiency of SM22α enhanced the interaction of VSMCs with macrophages. Macrophages were retained and activated by Sm22α-/- VSMCs via upregulating VCAM-1 expression. The ratio of apoptosis was increased by 1.62-fold in VSMCs treated with the conditional media (CM) from activated RAW264.7 cells, compared to that of the control CM ( P < 0.01 ), and apoptosis of Sm22α-/- VSMCs was higher than that of WT VSMCs ( P < 0.001 ). Next, circRasGEF1B from activated macrophages was delivered into VSMCs promoting ZFP36 expression via stabilization of ZFP36 mRNA. Importantly, circRasGEF1B, as a scaffold, guided ZFP36 to preferentially bind to and decay Bcl-2 mRNA in a sequence-specific manner and triggered apoptosis of VSMCs, especially in Sm22α-/- VSMCs. These findings reveal a novel mechanism by which the circRasGEF1B-ZFP36 axis mediates macrophage-induced VSMC apoptosis via decay of Bcl-2 mRNA, whereas Sm22α-/- VSMCs have a higher sensitivity to apoptosis.

scholarly journals Vascular Smooth Muscle Cells in Aortic Aneurysm: From Genetics to Mechanisms

2021 ◽  
Author(s):  
Haocheng Lu ◽  
Wa Du ◽  
Lu Ren ◽  
Milton H. Hamblin ◽  
Richard C. Becker ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Thoracic Aortic Aneurysm ◽  
Muscle Cells ◽  
Abdominal Aortic ◽  
Aneurysm Development

Abstract Aortic aneurysm, including thoracic aortic aneurysm and abdominal aortic aneurysm, is the second most prevalent aortic disease following atherosclerosis, representing the ninth‐leading cause of death globally. Open surgery and endovascular procedures are the major treatments for aortic aneurysm. Typically, thoracic aortic aneurysm has a more robust genetic background than abdominal aortic aneurysm. Abdominal aortic aneurysm shares many features with thoracic aortic aneurysm, including loss of vascular smooth muscle cells (VSMCs), extracellular matrix degradation and inflammation. Although there are limitations to perfectly recapitulating all features of human aortic aneurysm, experimental models provide valuable tools to understand the molecular mechanisms and test novel therapies before human clinical trials. Among the cell types involved in aortic aneurysm development, VSMC dysfunction correlates with loss of aortic wall structural integrity. Here, we discuss the role of VSMCs in aortic aneurysm development. The loss of VSMCs, VSMC phenotypic switching, secretion of inflammatory cytokines, increased matrix metalloproteinase activity, elevated reactive oxygen species, defective autophagy, and increased senescence contribute to aortic aneurysm development. Further studies on aortic aneurysm pathogenesis and elucidation of the underlying signaling pathways are necessary to identify more novel targets for treating this prevalent and clinical impactful disease.

scholarly journals Up-regulated MCPIP1 in abdominal aortic aneurysm is associated with vascular smooth muscle cell apoptosis and MMPs production

2019 ◽  
Vol 39 (11) ◽  
Author(s):  
Ming Xue ◽  
Gang Li ◽  
Dan Li ◽  
Zhu Wang ◽  
Lei Mi ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Vascular Smooth Muscle ◽  
Interleukin 1 ◽  
Ang Ii ◽  
Monocyte Chemotactic Protein ◽  
Abdominal Aortic ◽  
Chemotactic Protein ◽  
Proliferation And Apoptosis

Abstract Abdominal aortic aneurysm (AAA) is often clinically silent before rupture characterized by extensive vascular inflammation and degenerative elasticity of aortic wall. Monocyte chemotactic protein-induced protein-1 (MCPIP1) exhibits anti-infllammatory and pro-apoptotic effects involved in atherogenesis. However, little is known about the expression and the contribution of MCPIP1 in AAA. In the present study, we collected clinical AAA specimens and constructed AAA mice model through Ang-II infusion, and found apparently increased MCPIP1 expression and severe inflammatory infiltration in AAA aortic membrane as evidenced by elevated levels of monocyte chemotactic protein 1 (MCP-1), interleukin 1 β (IL-1β) and NF-κB, as well as HE staining. The elasticity of aortic tunica media was impaired along with multiple apoptosis of vascular smooth muscle cells (VSMCs) in Ang-II-induced aneurysmal mouse. In vitro Ang-II administration of VSMCs induced MCPIP1 expression, accompanied by up-regulation of matrix metalloproteinase (MMP) 2 (MMP-2) and MMP-9, as well as enhancement of VSMCs proliferation and apoptosis, which may cause damage of intima–media elasticity. Silencing MCPIP1 reversed above effects to further restore the balance of proliferation and apoptosis in VSMCs. Overall, our data indicated that up-regulation of MCPIP1 may become a promising candidate for the diagnosis of AAA, and specific knockdown of MCPIP1 in VSMCs could inhibit VSMCs apoptosis and down-regulate MMPs to maintain vascular wall elasticity. Therefore, knockdown of MCPIP1 may serve as a potential target for gene therapy of AAA.

Abstract 534: Deficiency of Protease-activated Receptor 2 Attenuates Angiotensin II-induced Abdominal Aortic Aneurysm Independent of Vascular Smooth Muscle Cell Tissue Factor

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
David E Hall ◽  
Adrien Mann ◽  
Shannon M Jones ◽  
Nigel Mackman ◽  
A. Phillip Owens
Keyword(s):  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Vascular Smooth Muscle ◽  
Tissue Factor ◽  
Factor Xa ◽  
Male Mice ◽  
Abdominal Aortic ◽  
Protease Activated Receptor 2

Objective: Tissue factor (TF) is constitutively expressed in subendothelial cells, including vascular smooth muscle cells (VSMCs), and maintains hemostasis. The TF/factor VIIa complex as well as factor Xa have been shown to activate protease-activated receptor 2 (PAR-2). We and others have shown that TF/FVIIa-PAR-2 signaling induces migration of VSMCs in vitro and this is reduced in TF and PAR-2 deficient cells. We previously demonstrated C57BL/6 mice with 1% of normal TF levels (Low TF mice) had increased suprarenal abdominal aortic diameter and incidence of abdominal aortic aneurysm (AAA) compared to littermate controls. However, the source of cellular TF and whether signaling occurred through PAR-2 has not been examined. Our objective was to determine the importance of VSMC-specific deletion of TF and PAR-2 deficiency on the etiology of AAA. Methods and Results: VSMC-specific TF deficiency was evaluated on a low-density lipoprotein receptor deficient (Ldlr -/- ) background. Male mice were fed a fat-enriched diet (21% milk fat) and infused with angiotensin II (AngII; 1,000 ng/kg/min) for 28 days. Ldlr -/- /TF flox/flox SM22αCre + mice had increased abdominal aortic luminal diameters (Cre + : 1.92 ± 0.16 (n = 12); Cre - : 1.22 ± 0.03 mm (n = 10); P = 0.001) and incidence of AAA (100% vs. 50%; P = 0.01) compared to Cre - littermates. Next, we determined the effects of PAR-2 deficiency in AAA. Ldlr -/- /PAR-2 +/+ (n = 12) and Ldlr -/- /PAR-2 -/- (n = 15) male mice were fed a fat-enriched diet and infused with AngII for 28 days. PAR-2 deficiency attenuated abdominal aortic luminal diameters (PAR-2 +/+ : 1.78 ± 0.06 mm; PAR2 -/- : 1.17 ± 0.03 mm; P = 0.001) and incidence of AAA (84% versus 40%; P = 0.048) when compared to littermate controls. Total plasma cholesterol concentrations, lipoprotein cholesterol distributions, or increased systolic blood pressure was not different between groups. Conclusion: These results suggest that TF limits AAA growth and incidence via VSMCs in a PAR-2-independent manner. To verify this hypothesis, studies are currently underway to determine the effect of Factor Xa (FXa) inhibitors in PAR-2 deficient mice.

Abstract 019: Vascular Smooth Muscle ADAM17 Contributes To Angiotensin II-induced Abdominal Aortic Aneurysm Formation But Not Hypertension In Mice

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Toshiyuki Tsuji ◽  
Takehiko Takayanagi ◽  
Katherine Elliott ◽  
Takashi Obama ◽  
Kevin Crawford ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Vascular Smooth Muscle ◽  
Saline Infusion ◽  
Internal Diameter ◽  
Egfr Activation ◽  
Abdominal Aortic

Enhancement of the renin angiotensin II (AngII) system has been implicated in the development of abdominal aortic aneurysm (AAA). However, detailed molecular mechanism(s) by which AngII promotes AAA remain uncertain. We have demonstrated the critical role of a metalloprotease, ADAM17, in AngII-induced EGFR transactivation and subsequent hypertrophy in vascular smooth muscle cells (VSMC). In caveolin 1-/- mice, AAA formation induced by AngII plus beta-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, was attenuated. The attenuation of AAA formation was associated with suppression of ADAM17 induction and EGFR activation. Others have reported that systemic ADAM17 silencing attenuated CaCl2-induced AAA formation in mice. However, the cell type specific mechanism that is mediating the deleterious effect of ADAM17 in AAA is not well understood. Here, we tested our hypothesis that VSMC ADAM17 activation is required for AngII-promoted AAA formation using ADAM17flox/flox mice bred with sm22a Cre mice. 8 week old mice were co-infused with AngII 1000 ng/kg/min (4w) and BAPN 150 mg/kg/day (2w) or control saline (4w), and AAA formation was evaluated by echo (internal diameter) and measurement (external diameter) of the aortae. In control Cre-/- mice with the co-infusion, 52.4% (11/21) were dead due to aortic rupture/dissection. All surviving Cre-/- mice with co-infusion had AAA with max external/internal diameter (mm) of 2.18±0.55/1.75±0.33 vs 1.01±0.22/1.06±0.02 with saline infusion (p<0.01). In contrast, VSMC ADAM17 deficient Cre+/- with co-infusion did not die or develop AAA. The max external/internal diameter (mm) of AA in Cre+/- with co-infusion was 1.03±0.11/1.05±0.05 vs 1.01±0.12/1.27±0.21 with saline infusion. In contrast, both Cre-/- and +/- mice with the co-infusion developed hypertension assessed by telemetry (MAP mmHg: 161±15 vs 154±12). The ADAM17 deletion was also associated with less EGFR activation, ER/oxidative stress and extravascular fibrosis/matrix deposition. In conclusion, VSMC ADAM17 appears to be a critical metalloprotease contributing to AAA formation but not hypertension induced by AngII + BAPN. The mechanism by which VSMC ADAM17 promotes AAA seems to involve activation of EGFR and induction of ER/oxidative stress.

Sign in / Sign up

Export Citation Format

Share Document