scholarly journals Cezanne is a critical regulator of pathological arterial remodelling by targeting β-catenin signalling

2021 ◽  
Author(s):  
Weiwei An ◽  
Le A Luong ◽  
Neil P Bowden ◽  
Mei Yang ◽  
Wei Wu ◽  
...  
Keyword(s):  
Neointimal Hyperplasia ◽  
Kidney Injury ◽  
Vascular Diseases ◽  
Negative Regulator ◽  
Deubiquitinating Enzyme ◽  
Ccn Family ◽  
Expression Levels ◽  
Vsmc Proliferation ◽  
Atherosclerotic Lesions ◽  
And Migration

Abstract Aims Pathological arterial remodelling including neointimal hyperplasia and atherosclerosis is the main underlying cause for occluding arterial diseases. Cezanne is a novel deubiquitinating enzyme, functioning as a NF-кB negative regulator, and plays a key role in renal inflammatory response and kidney injury induced by ischaemia. Here we attempted to examine its pathological role in vascular smooth muscle cell (VSMC) pathology and arterial remodelling. Methods and results Cezanne expression levels were consistently induced by various atherogenic stimuli in VSMCs, and in remodelled arteries upon injury. Functionally, VSMCs over-expressing wild-type Cezanne, but not the mutated catalytically-inactive Cezanne (C209S), had an increased proliferative ability and mobility, while the opposite was observed in VSMCs with Cezanne knockdown. Surprisingly, we observed no significant effects of Cezanne on VSMC apoptosis, NF-κB signalling, or inflammation. RNA-sequencing and biochemical studies showed that Cezanne drives VSMC proliferation by regulating CCN family member 1 (CCN1) by targeting β-catenin for deubiquitination. Importantly, local correction of Cezanne expression in the injured arteries greatly decreased VSMC proliferation, and prevented arterial inward remodelling. Interestingly, global Cezanne gene deletion in mice led to smaller atherosclerotic plaques, but with a lower level of plaque stability. Translating, we observed a similar role for Cezanne in human VSMCs, and higher expression levels of Cezanne in human atherosclerotic lesions. Conclusion Cezanne is a key regulator of VSMC proliferation and migration in pathological arterial remodelling. Our findings have important implications for therapeutic targeting Cezanne signalling and VSMC pathology in vascular diseases.

scholarly journals MIA SH3 Domain ER Export Factor 3 Deficiency Prevents Neointimal Formation by Restoring BAT-Like PVAT and Decreasing VSMC Proliferation and Migration

2021 ◽  
Vol 12 ◽  
Author(s):  
Yu Lei ◽  
Jianfei Xu ◽  
Mengju Li ◽  
Ting Meng ◽  
Meihua Chen ◽  
...  
Keyword(s):  
Vascular Remodeling ◽  
Association Studies ◽  
Neointimal Hyperplasia ◽  
Vascular Diseases ◽  
Genome Wide Association Studies ◽  
Neointimal Formation ◽  
Vsmc Proliferation ◽  
And Migration ◽  
Er Export ◽  
Proliferation And Migration

Abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) and excessive accumulation of dysfunctional PVAT are hallmarks of pathogenesis after angioplasty. Recent genome-wide association studies reveal that single-nucleotide polymorphism (SNP) in MIA3 is associated with atherosclerosis-relevant VSMC phenotypes. However, the role of MIA3 in the vascular remodeling response to injury remains unknown. Here, we found that expression of MIA3 is increased in proliferative VSMCs and knockdown of MIA3 reduces VSMCs proliferation, migration, and inflammation, whereas MIA3 overexpression promoted VSMC migration and proliferation. Moreover, knockdown of MIA3 ameliorates femoral artery wire injury-induced neointimal hyperplasia and increases brown-like perivascular adipocytes. Collectively, the data suggest that MIA3 deficiency prevents neointimal formation by decreasing VSMC proliferation, migration, and inflammation and maintaining BAT-like perivascular adipocytes in PVAT during injury-induced vascular remodeling, which provide a potential therapeutic target for preventing neointimal hyperplasia in proliferative vascular diseases.

Abstract 15691: The Novel High Mobility Group Protein Hmgxb4 Promotes Neointimal Formation in Response to Arterial Injury

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
xiangqin he ◽  
Kunzhe Dong ◽  
Jian Shen ◽  
Islam Osman ◽  
Guoqing Hu ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Neointimal Hyperplasia ◽  
Critical Role ◽  
High Mobility ◽  
Arterial Injury ◽  
The Novel ◽  
Neointimal Formation ◽  
Vsmc Proliferation ◽  
And Migration

Introduction: Restenosis after percutaneous intervention is predominantly attributed to proliferation and migration of vascular smooth muscle cells (VSMCs). However, the key regulators responsible for VSMC proliferation and migration remain to be identified. Hypothesis: We previously reported that the novel high mobility group (HMG) nuclear protein HMGXB4 (HMG-Box containing 4) plays a critical role in the de-differentiation of vascular smooth muscle cells in vitro and in acute inflammatory response to septic shock. We hypothesize that HMGXB4 is critical for neointimal hyperplasia in response to inflammatory stimuli. Methods and Results: We found that the expression of HMGXB4 is dramatically induced in ligation or wire injury-induced neointimal hyperplasia and correlated with the activation of inflammatory signaling in mice. Using an inducible smooth muscle-specific Hmgxb4 KO (knockout) mice model, we found specific KO of Hmgxb4 in VSMCs ameliorates ligation- or wire- injury induced neointimal formation. Among an array of growth factors and inflammation cytokines, we found that TNFα and INFγ effectively induces the expression of HMGXB4 in VSMCs and correlates with the VSMC proliferation in vitro. Furthermore, we found deletion of HMGXB4 attenuates while over-expression of HMGXB4 promotes inflammation cytokines-induced VSMC proliferation in vitro. These results suggest injury-induced inflammatory signal triggers HMGXB4 induction, which, in turn, promotes the VSMC proliferation and neointimal formation. Conclusions: Our study not only demonstrates a critical role of HMGXB4 in promoting neointimal hyperplasia in response the arterial injury, but also suggests HMGXB4 is a potential novel target for the management of restenosis in human.

scholarly journals BOP1 Knockdown Attenuates Neointimal Hyperplasia by Activating p53 and Inhibiting Nascent Protein Synthesis

2021 ◽  
Vol 2021 ◽  
pp. 1-20
Author(s):  
Fangyuan Jia ◽  
Qi Wu ◽  
Zhiwei Wang ◽  
Min Zhang ◽  
Shun Yuan ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Stress Response ◽  
Ribosome Biogenesis ◽  
Biological Effects ◽  
Neointimal Hyperplasia ◽  
Neointimal Formation ◽  
Vsmc Proliferation ◽  
Stress Response Pathway ◽  
And Migration ◽  
Proliferation And Migration

The rate of ribosome biogenesis plays a vital role in cell cycle progression and proliferation and is strongly connected with coronary restenosis and atherosclerosis. Blocking of proliferation 1 (BOP1) has been found as an evolutionarily conserved gene and a pivotal regulator of ribosome biogenesis and cell proliferation. However, little is known about its role in neointimal formation and its relationship with vascular smooth muscle cell (VSMC) proliferation and migration. The present study mainly explores the effect of BOP1 on VSMCs, the progression of neointimal hyperplasia, and the pathogenic mechanism. The expression of BOP1 was found to be significantly elevated during neointimal formation in human coronary samples and the rat balloon injury model. BOP1 knockdown inspires the nucleolus stress, which subsequently activates the p53-dependent stress response pathway, and inhibits the nascent protein synthesis, which subsequently inhibits the proliferation and migration of VSMCs. Knockdown ribosomal protein L11 (RPL11) by transfecting with siRNA or inhibiting p53 by pifithrin-α (PFT-α) partly reserved the biological effects induced by BOP1 knockdown. The present study revealed that BOP1 deletion attenuates VSMC proliferation and migration by activating the p53-dependent nucleolus stress response pathway and inhibits the synthesis of nascent proteins. BOP1 may become a novel biological target for neointimal hyperplasia.

scholarly journals Plant-Derived Products for Treatment of Vascular Intima Hyperplasia Selectively Inhibit Vascular Smooth Muscle Cell Functions

2018 ◽  
Vol 2018 ◽  
pp. 1-17 ◽  
Author(s):  
Kang Xu ◽  
Mohanad Kh Al-ani ◽  
Xin Pan ◽  
Qingjia Chi ◽  
Nianguo Dong ◽  
...  
Keyword(s):  
Natural Products ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Neointimal Hyperplasia ◽  
Critical Role ◽  
Vascular Endothelial Cell ◽  
Signal Pathways ◽  
Vsmc Proliferation ◽  
Cell Functions ◽  
And Migration

Natural products are used widely for preventing intimal hyperplasia (IH), a common cardiovascular disease. Four different cells initiate and progress IH, namely, vascular smooth muscle, adventitial and endothelial cells, and circulation or bone marrow-derived cells. Vascular smooth muscle cells (VSMCs) play a critical role in initiation and development of intimal thickening and formation of neointimal hyperplasia. In this review, we describe the different originating cells involved in vascular IH and emphasize the effect of different natural products on inhibiting abnormal cellular functions, such as VSMC proliferation and migration. We further present a classification for the different natural products like phenols, flavonoids, terpenes, and alkaloids that suppress VSMC growth. Abnormal VSMC physiology involves disturbance in MAPKs, PI3K/AKT, JAK-STAT, FAK, and NF-κB signal pathways. Most of the natural isolate studies have revealed G1/S phase of cell cycle arrest, decreased ROS production, induced cell apoptosis, restrained migration, and downregulated collagen deposition. It is necessary to screen optimal drugs from natural sources that preferentially inhibit VSMC rather than vascular endothelial cell growth to prevent early IH, restenosis following graft implantation, and atherosclerotic diseases.

Inhibitory Effects of Brazilin on the Vascular Smooth Muscle Cell Proliferation and Migration Induced by PDGF-BB

2013 ◽  
Vol 41 (06) ◽  
pp. 1283-1296 ◽  
Author(s):  
Jing Guo ◽  
Li Li ◽  
Yu-Jie Wu ◽  
Yu Yan ◽  
Xiao-Na Xu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Diseases ◽  
Inhibitory Effects ◽  
Vsmc Proliferation ◽  
And Migration ◽  
Proliferation And Migration

Abnormal vascular smooth muscle cell (VSMC) proliferation and migration contribute to the pathogenesis of vascular diseases including atherosclerosis and restenosis. Brazilin isolated from the heartwood of Caesalpinia sappan L. has been reported to exhibit various biological activities, such as anti-platelet aggregation, anti-inflammation, vasorelaxation and pro-apoptosis. However, the functional effects of Brazilin on VSMCs remain unexplored. The present study investigated the potential effects of Brazilin on platelet-derived growth factor (PDGF)-BB induced VSMC proliferation and migration as well as the underlying mechanism of action. VSMC proliferation and migration were measured by Crystal Violet Staining, wound-healing and Boyden chamber assays, respectively. Cell cycle was analyzed by flow cytometry. Enzymatic action of matrix metalloproteinase-9 (MMP-9) was carried out by gelatin zymography. Expression of adhesion molecules, cell cycle regulatory proteins, the phosphorylated levels of PDGF receptor β (PDGF-Rβ), Src, extracellular signal regulated kinase (ERK) and Akt were tested by immunoblotting. The present study demonstrated that pretreatment with Brazilin dose-dependently inhibited PDGF-BB stimulated VSMC proliferation and migration, which were associated with a cell-cycle arrest at G0/G1 phase, a reduction in the adhesion molecule expression and MMP-9 activation in VSMCs. Furthermore, the increase in PDGF-Rβ, Src, ERK1/2 and Akt phosphorylation induced by PDGF-BB were suppressed by Brazilin. These findings indicate that Brazilin inhibits PDGF-BB induced VSMC proliferation and migration, and the inhibitory effects of Brazilin may be associated with the blockade of PDGF-Rβ - ERK1/2 and Akt signaling pathways. In conclusion, the present study implicates that Brazilin may be useful as an anti-proliferative agent for the treatment of vascular diseases.

Adipocyte factor CTRP6 inhibits homocysteine-induced proliferation, migration, and dedifferentiation of vascular smooth muscle cells through PPARγ/NLRP3

2021 ◽  
pp. 1-10
Author(s):  
JiLi Liu ◽  
XiaoNing Yan ◽  
ZhaoLin Wang ◽  
Na Zhang ◽  
AnHua Lin ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Vascular Diseases ◽  
Muscle Cells ◽  
Underlying Mechanism ◽  
Regulatory Relationship ◽  
Vsmc Proliferation ◽  
And Migration

NLRP3 and PPARγ play important roles in the development of atherosclerosis (AS). Studies have shown that PPARγ regulates the expression of NLRP3 in vascular diseases. In addition, the adipocyte factor CTRP6 can improve the activation of PPARγ in vascular diseases. However, the regulatory relationship between CTRP6, PPARγ, and NLRP3 in AS and its underlying mechanism have not been reported. Since proliferation, migration, and dedifferentiation of vascular smooth muscle cells (VSMCs) are key events in AS, in this study, we induced proliferation, migration, and dedifferentiation of VSCMs through homocysteine (HCY) to detect the specific effects of CTRP6, PPARγ, and NLRP3. Subsequently, CTRP6 was overexpressed and the PPARγ inhibitor GW9662 and agonist rosiglitazone were administered to HCY-induced VSCMs to investigate the mechanisms. The results show that the expression of CTRP6 decreased in HCY-induced VSMCs. In addition, CTRP6 overexpression inhibited the proliferation and migration of HCY-induced VSMCs, as well as cell cycle acceleration and dedifferentiation. Overexpression of CTRP6 increased HCY-induced PPARγ expression and inhibited NLRP3 expression. The addition of GW9662 and rosiglitazone further demonstrated that overexpression of CTRP6 inhibited HCY-induced VSMC proliferation, migration, and dedifferentiation through PPARγ/NLRP3 signaling. In conclusion, CTRP6 inhibited HCY-induced proliferation, migration, and dedifferentiation of VSMCs through PPARγ/NLRP3.

scholarly journals TAT-Beclin1 Represses the Carcinogenesis of DUSP4-positive PTC by Enhancing Autophagy

2021 ◽  
Author(s):  
Leilei Zang ◽  
Yanmei Song ◽  
Yanhua Tian ◽  
Ning Hu
Keyword(s):  
Negative Regulator ◽  
Expression Levels ◽  
Autophagic Activity ◽  
Lc3 Puncta ◽  
And Migration ◽  
Cancer Tissues ◽  
The Relationship ◽  
Autophagic Proteins ◽  
Immunohistochemical Analyses

Abstract Background: DUSP4 is a pro-tumorigenic molecule of papillary thyroid carcinoma (PTC). DUSP4 also exists as an autophagic regulator. Moreover, DUSP4, as a negative regulator of MAPK, can prevent Beclin1 from participating in autophagic response. This study aimed to explore whether TAT-Beclin1, a recombinant protein of Beclin1, could inhibit the tumorigenesis of DUSP4-positive PTC by regulating autophagy.Methods: First, we divided PTC cancer tissues into three groups according to DUSP4 expression levels by immunohistochemical analyses, and evaluated the relationship between the expression of autophagic proteins (Beclin1 and LC3II) and DUSP4 expression using Western blotting assays. After overexpression of DUSP4 by lentiviral transduction, the roles of TAT-Beclin1 on DUSP4-overexpressed PTC was detected.Results: Our results showed that the expression levels of autophagic proteins (Beclin1 and LC3II) increased with the increase of DUSP4 expression in PTC carcinomas. In PTC cells, DUSP4 overexpression-inhibited autophagic activity (including Beclin1 expression, LC3 conversion rate and LC3-puncta formation) and -promoted cell proliferation and migration were reversed by TAT-Beclin1 administration. In vivo assays also showed that DUSP4-overexpressed PTC cells had stronger tumorigenic ability and weaker autophagic activity, which was recovered by TAT-Beclin1 administration. Conclusions: TAT-Beclin1, as an autophagic promoter, could repress the carcinogenesis of DUSP4-positive PTC, which implies that the addition of TAT-Beclin1 may be determined through detecting the levels of DUSP4 in the treatment of PTC.

scholarly journals Sclerostin and Vascular Pathophysiology

2020 ◽  
Vol 21 (13) ◽  
pp. 4779 ◽  
Author(s):  
Antonino Catalano ◽  
Federica Bellone ◽  
Nunziata Morabito ◽  
Francesco Corica
Keyword(s):  
Wnt Signaling ◽  
Vascular System ◽  
Foam Cell ◽  
Current Knowledge ◽  
Wnt Signaling Pathway ◽  
Cell Formation ◽  
Vascular Diseases ◽  
Negative Regulator ◽  
Foam Cell Formation ◽  
And Migration

There is cumulating evidence for a contribution of Wnt signaling pathways in multiple processes involved in atherosclerosis and vascular aging. Wnt signaling plays a role in endothelial dysfunction, in the proliferation and migration of vascular smooth muscle cells (VSMCs) and intimal thickening. Moreover, it interferes with inflammation processes, monocyte adhesion and migration, as well as with foam cell formation and vascular calcification progression. Sclerostin is a negative regulator of the canonical Wnt signaling pathway and, accordingly, the consequence of increased sclerostin availability can be disruption of the Wnt signalling cascade. Sclerostin is becoming a marker for clinical and subclinical vascular diseases and several lines of evidence illustrate its role in the pathophysiology of the vascular system. Sclerostin levels increase with aging and persist higher in some diseases (e.g., diabetes, chronic kidney disease) that are known to precipitate atherosclerosis and enhance cardiovascular risk. Current knowledge on the association between sclerostin and vascular diseases is summarized in this review.

scholarly journals Fisetin Alleviates Neointimal Hyperplasia via PPARγ/PON2 Antioxidative Pathway in SHR Rat Artery Injury Model

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
Fang Pei ◽  
Hua Pei ◽  
Chunhua Su ◽  
Lin Du ◽  
Jifen Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Neointimal Hyperplasia ◽  
Hypertensive Patients ◽  
Vsmc Proliferation ◽  
And Migration ◽  
Proliferation And Migration

The phenotypic transformation of proliferation and migration in vascular smooth muscle cells (VSMCs) from media to intima is the basic pathology of neointimal hyperplasia after angioplasty in hypertensive patients. Angiotensin II (AngII) stimulates oxidative stress in VSMC, inducing VSMC proliferation and migration, which is a critical factor in both developments of hypertension and angioplasty-induced arterial restenosis. Fisetin, a plant flavonoid polyphenol, has been reported to be antioxidative and potent senolytic. It is unknown whether fisetin would inhibit neointimal hyperplasia. Therefore, we investigated the role of fisetin in neointimal formation in vitro and in vivo. The rat thoracic aortic smooth muscle cells (A10 cells) stimulated by AngII were used as the in vitro neointimal hyperplasia model, where AngII significantly induced the proliferation and migration in A10 cells. We found that fisetin could dose-dependently inhibit the effect of AngII via inducing the expression of an antioxidant, paraoxonase-2 (PON2), whose overexpression could inhibit the proliferation and migration of A10 cells and downexpression by siRNA had the opposite effect. Furthermore, we found the mechanism of fisetin’s inducing PON2 expression involved PPARγ. Rosiglitazone, a PPARγ agonist, could increase PON2 expression in A10 cells, while the PPARγ inhibitor prevented the effect of fisetin on PON2. The in vivo neointimal hyperplasia model was established 2 weeks after the carotid artery balloon injury in SHR rats. Administration of fisetin (ip 3 mg/kg daily for 2 weeks) right after the injury significantly increased PON2 expression in the artery, inhibiting ROS production, and efficiently reduced carotid neointimal hyperplasia. These results indicate that fisetin increases the expression of antioxidant PON2 via activation of PPARγ, reducing oxidative stress, inhibiting VSMC proliferation and migration, and alleviates neointimal hyperplasia after intimal injury. PON2 may be a potential therapeutic target to reduce arterial remodeling after angioplasty in hypertensive patients.

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