ACTA BIOCHIMICA ET BIOPHYSICA SINICA
·
2024
·
IF 3.3
Yanyan Heng,Wei Wei,Linzhong Cheng,Feifei Wu,Haoyu Dong,Jingxia Li,Jianing Fu,Bingjie Yang,Xinyue Liang,Chunyan Liu,Haiju Li,Haihua Liu,Pengfei Zhang
Diabetes accelerates vascular senescence, which is the basis for atherosclerosis and stiffness. The activation of the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome and oxidative stress are closely associated with progressive senescence in vascular smooth muscle cells (VSMCs). The vascular protective effect of FGF21 has gradually gained increasing attention, but its role in diabetes-induced vascular senescence needs further investigation. In this study, diabetic mice and primary VSMCs are transfected with an FGF21 activation plasmid and treated with a peroxisome proliferator-activated receptor γ (PPARγ) agonist (rosiglitazone), an NLRP3 inhibitor (MCC950), and a spleen tyrosine kinase (SYK)-specific inhibitor, R406, to detect senescence-associated markers. We find that FGF21 overexpression significantly restores the level of catalase (CAT), vascular relaxation, inhibits the intensity of ROSgreen fluorescence and p21 immunofluorescence, and reduces the area of SA-β-gal staining and collagen deposition in the aortas of diabetic mice. FGF21 overexpression restores CAT, inhibits the expression of p21, and limits the area of SA-β-gal staining in VSMCs under high glucose conditions. Mechanistically, FGF21 inhibits SYK phosphorylation, the production of the NLRP3 dimer, the expression of NLRP3, and the colocalization of NLRP3 with PYCARD (ASC), as well as NLRP3 with caspase-1, to reverse the cleavage of PPARγ, preserve CAT levels, suppress ROSgreen density, and reduce the expression of p21 in VSMCs under high glucose conditions. Our results suggest that FGF21 alleviates vascular senescence by regulating the SYK-NLRP3 inflammasome-PPARγ-catalase pathway in diabetic mice.
研究领域:
内分泌学
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心血管生物学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR MEDICINE-JMM
·
2025
·
IF 4.2
Wen Xin,Peng Yuefeng,Yang Wenqing,Zhu Yuzhong,Yu Fan,Geng Li,Wang Xianfeng,Wang Xiaoyan,Zhang Xiaodong,Tang Yi,Feng Lei,Zhou Tingting,Jia Hongliang,Yang Liu
Transient receptor potential canonical 1 (TRPC1) channel, a Ca 2+ -permeable ion channel widely expressed in vasculature, has been reported to be involved in various cardiovascular disorders. However, the pathophysiological function of vascular smooth muscle cell (VSMC)-derived TRPC1 in hypertension and hypertensive cardiovascular remodeling remains to be defined. In this study, we found increased TRPC1 expression in both angiotensin II (AngII)-treated VSMCs and aortas from AngII-infused mice. VSMC-specific TRPC1 deficiency strikingly attenuated AngII-induced vasoconstriction, hypertension, vascular remodeling, and cardiac hypertrophy. Mechanistically, AngII activated enhancer of zeste homolog 2 (EZH2) to stimulate TRPC1 expression, induced calcium influx and phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK-ERK), which in turn triggered VSMC proliferation and migration and exacerbated hypertension and cardiovascular remodeling. Treatment with EZH2 inhibitor reduced VSMC proliferation and migration and alleviated vasoconstriction and hypertension in AngII-infused mice. Together, we revealed the pathogenic role of the EZH2-TRPC1-MEK/ERK pathway in AngII-induced hypertension and cardiovascular damage. TRPC1 or EZH2 inhibition may represent a desirable therapeutic target for the treatment of hypertension. Key messages
AngII activates AT1R-EZH2-TRPC1 pathway in VSMCs and aortas of hypertensive mice.
TRPC1 promotes VSMC proliferation and migration via MEK/ERK signaling.
Inhibition of TRPC1 or EZH2 alleviates hypertension and cardiovascular remodeling.
研究领域:
心血管病学
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分子生物学
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药理学
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产品关联
DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2024
·
IF 6.9
Zhang Bu-chun,Zhu Wen-ya,Wang Sheng-nan,Zhu Meng-meng,Ma Hui,Dong Liang,Yang Xiao-xiao,Ma Chuan-rui,Ma Li-kun,Chen Yuan-li
Vascular smooth muscle cell (VSMC) phenotype transformation significantly contributes to vascular intimal hyperplasia. However, effective preventive and therapeutic measures are lacking. Colchicine, a binary alkaloid derived from Colchicum autumnale , is traditionally used for treating inflammatory diseases. Its role in neointima formation is not fully understood. Here, we investigated the role of colchicine in vascular intimal hyperplasia. We found that colchicine significantly reduced vascular intimal hyperplasia in an animal model at 7, 14, and 28 days post carotid artery ligation and increased the number of contractile-phenotype VSMCs (SMA-positive cells) in the neointimal areas. In vitro experiments demonstrated that colchicine facilitated the transition of VSMCs from a proliferative phenotype to a contractile phenotype. Additionally, colchicine attenuated PDGF-BB-induced phenotypic conversion and upregulated the expression of serum response factor (SRF) and myocardin (MYOCD). Further molecular mechanistic studies revealed that colchicine inhibited the expression of forkhead box protein O3A (FOXO3A) to increase the activation of the SRF‒MYOCD complex. FOXO3A can bind to MSX1/2, thereby inhibiting the expression of SRF–MYOCD and contractile genes. Moreover, colchicine maintains vascular homeostasis and stabilizes the contractile phenotype by affecting the expression of autophagy-related genes (LC3II, p62, and Beclin-1) induced by FOXO3A. Additionally, colchicine inhibited monocyte/macrophage infiltration and inflammatory cytokine expression. In summary, this study suggests that colchicine inhibits vascular intimal hyperplasia by modulating FOXO3A-mediated SRF-MYOCD activation and autophagy, providing new insights for future therapeutic approaches targeting occlusive vascular diseases.
研究领域:
药理学
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心血管疾病
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Molecular Therapy-Nucleic Acids
·
2021
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IF 8.886
Tingyu Zong,Yanyan Yang,Xiaotong Lin,Shaoyan Jiang,Hui Zhao,Meixin Liu,Yuanyuan Meng,Yong Li,Liang Zhao,Guozhang Tang,Kun Gong,Zhibin Wang,Tao Yu
Accumulating evidence shows that tRNA-derived fragments are a novel class of functional small non-coding RNA; however, their roles in aortic dissection (AD) are still unknown. In this study, we found that 5′-tiRNA-Cys-GCA was significantly downregulated in human and mouse models of aortic dissection. The abnormal proliferation, migration, and phenotypic transition of vascular smooth muscle cells (VSMCs) played a crucial role in the initiation and progression of aortic dissection, with 5′-tiRNA-Cys-GCA as a potential phenotypic switching regulator, because its overexpression inhibited the proliferation and migration of VSMCs and increased the expression of contractile markers. In addition, we verified that signal transducer and activator of transcription 4 (STAT4) was a direct downstream target of 5′-tiRNA-Cys-GCA. We found that the STAT4 upregulation in oxidized low-density lipoprotein (ox-LDL)-treated VSMCs, which promoted cell proliferation, migration, and phenotypic transformation, was reversed by 5′-tiRNA-Cys-GCA. Furthermore, 5′-tiRNA-Cys-GCA treatment reduced the incidence and prevented the malignant process of angiotensin II- and β-aminopropionitrile-induced AD in mice. In conclusion, our findings reveal that 5′-tiRNA-Cys-GCA is a potential regulator of the AD pathological process via the STAT4 signaling pathway, providing a novel clinical target for the development of future treatment strategies for aortic dissection.
研究领域:
心血管疾病
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分子生物学
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非编码RNA
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病理生理学
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产品关联
DOI
PubMed
高影响因子
CHEMICAL ENGINEERING JOURNAL
·
2026
·
IF 12.5
Xianru Bi,Yuxuan Xiao,Rongjie Zhang,Wei Sun,Yu Li,Chao Qi,Jiqin Lian,Lu Lu,Yingxue Hao
Abdominal aortic aneurysm (AAA) is a cardiovascular disease with extremely high mortality rate, yet its treatment options are still limited in the clinic. This study presents a carrier-free dual-drug nanoplatform to therapeutically reprogram macrophage fate for improving AAA treatment efficacy. The nanoplatform was synthesized through the self-assembly of naringenin (NGN) and rapamycin (RAP) and modified with DSPE-PEG 2K and DSPE-PEG 2K -cRGD (named RNR NPs) to confer AAA targeting capability. The RNR NPs could efficiently accumulate in AAA site after systemic administration for on-demand delivery of the NGN/RAP drug combination to vascular smooth muscle cells (VSMCs) and residing M1-like macrophages. Here the NGN and RAP components could cooperatively activate the transcription factor EB (TFEB) signaling in the AAA-residing pro-inflammatory M1-like macrophages to reprogram them into an anti-inflammatory M2-like phenotype to reverse local inflammation. Meanwhile, they could also scavenge reactive oxygen species in VSMCs and inhibit apoptosis signaling to inhibit VSMCs apoptosis and calcification. These effects could act in a cooperative manner for effectively ameliorating AAA symptoms in vivo . Overall, the RNR NPs present an approach for the efficient treatment of AAA in the clinic with optimal safety.
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产品关联
DOI
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
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IF 5.6
Haijun Wang,Bao Jing,Xinyu Dong,Muning Wang,Yan Xuan,Siyao Chang,Yuxin Qin,Bojian Zhang,Weizhong Zhou,Sheng Wang,Yufeng Lin,Zhiyang Han
Vascular smooth muscle cells (VSMCs) are essential for maintaining vascular tone and participate in all stages of atherosclerosis. The transition of VSMCs into macrophage-like cells is a major source of plaque foam cells. Nevertheless, the mechanisms regulating this phenotypic transition remain elusive. RNA Binding Motif Protein 47 (RBM47) expression was increased by more than twofold in aortas of ApoE − / − mice and was markedly elevated in RBM47 + α-SMA + double-positive cells within atherosclerotic plaques. RBM47 knockdown significantly reduced plaque burden and vascular inflammation, and suppressed VSMC-to-macrophage-like transition. In POV-PC-treated VSMCs, RBM47 knockdown inhibited VSMC proliferation, migration, inflammation, and macrophage-like transition. Mechanistically, RBM47 was found to directly bind to two specific sequences within the 3′UTR of GALNT4 mRNA and enhance its stability. Functional rescue experiments confirmed that GALNT4 mediated the effects of RBM47 on VSMC-to-macrophage-like transition. These findings suggest that RBM47 contributes to atherosclerosis by stabilizing GALNT4 mRNA and promoting VSMC-to-macrophage-like transition.
✓ 已验证
产品关联
DOI
高影响因子
CELLULAR AND MOLECULAR LIFE SCIENCES
·
2026
·Vol. 83
·期 1
·141
·
IF 6.5
Jia Wang,Xuan Shi,Di Wang,Jie Gao,Kangmo Huang,Juanji Li,Weichen Dong,Yunzi Li,Hongquan Guo,Yi Wang,Zhenqian Huang,Zhihui Liu,Li Huang,Liangyuan Pan,Xinfeng Liu,Wusheng Zhu,Mengna Peng,Gelin Xu
Background Despite the use of lipid-lowering and anti-inflammatory treatments, the progression of atherosclerosis is relentless in most patients. This suggests the presence of in situ pathological factors that continuously exacerbate lesions. We hypothesized that extracellular vesicles (EVs) within the atherosclerotic microenvironment might act as in situ stimulatory factors on vascular smooth muscle cells (VSMCs), thereby exacerbating atherosclerosis. Methods and results A local atherosclerosis model was induced using Ldlr knockout ( Ldlr KO) rats fed a high-cholesterol diet and subjected to partial carotid ligation. Immunofluorescence, Western blot (WB), and single-cell sequencing confirmed the phenotypic switching of VSMCs in atherosclerotic plaques from both rats and humans. The phenotypic switching of VSMCs in atherosclerotic rats was characterized by reduced expression of VSMC contraction markers and increased expression of LGALS3, PDGFRB, and SCA1. GW4869 inhibited the phenotypic switching of VSMCs in atherosclerotic plaques in a rat model. EVs were extracted from atherosclerotic carotid tissues using differential centrifugation. Chitosan thermosensitive hydrogels were used for in situ delivery of EVs into the arterial wall of the carotid artery. Immunofluorescence staining revealed that atherosclerotic plaque-derived EVs (AS-EVs) promoted VSMC phenotypic switching and downregulated the expression of VSMC contractile markers in vitro. miRNA analysis of EVs derived from atherosclerotic plaques of rats identified miR-23a-3p and its target gene Myl12b . To investigate the underlying mechanisms, engineered EVs loaded with miR-23a-3p were used to mimic AS-EVs. AS-EVs potentially regulate MRTFA nuclear translocation via miR-23a-3p/ Myl12b , inhibit contractile marker expression, promote VSMC phenotypic switching, and further promote carotid artery remodelling. Conclusion We conclude that AS-EVs promote VSMC phenotypic switching and exacerbate atherosclerosis. Supplementary Information The online version contains supplementary material available at 10.1007/s00018-026-06094-4.
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产品关联
DOI
PubMed
高影响因子
PHYTOMEDICINE
·
2024
·
IF 6.7
Xiaoliang Dong,Lu Qu,Bingxin Wang,Xiaowei Sha,Bo Wu,Yudong Sun,Xiaohua Pan,Juan Xiong,Jia Sun,Li-Long Pan
ABSTRACT Background Cardiovascular disease is one of the main causes of global mortality, and there is an urgent need for effective treatment strategies. Gut microbiota-dependent metabolite trimethylamine-N-oxide (TMAO) promotes the development of cardiovascular diseases, and shizukaol C, a natural sesquiterpene isolated from Chloranthus multistachys with various biological activities, might exhibit beneficial role in preventing TMAO-induced vascular inflammation. Purpose The purpose of this study was to investigate the anti-inflammatory effects and the underlying mechanisms of shizukaol C on TMAO-induced vascular inflammation. Methods The effect and underlying mechanism of shizukaol C on TMAO-induced adhesion molecules expression, bone marrow-derived macrophages (BMDM) adhesion to VSMC were evaluated by western blot, cell adhesion assay, co-immunoprecipitation, immunofluorescence assay, and quantitative Real-Time PCR, respectively. To verify the role of shizukaol C in vivo , TMAO-induced vascular inflammation model were established using guidewire-induced injury on mice carotid artery. Changes in the intima area and the expression of GSTpi, VCAM-1, CD68 were examined using haematoxylin-eosin staining, and immunofluorescence assay. Results Our data demonstrated that shizukaol C significantly suppressed TMAO-induced adhesion molecule expression and the bone marrow-derived macrophages (BMDM) adhesion in vascular smooth muscle cells (VSMC). Mechanically, shizukaol C inhibited TMAO-induced c-Jun N-terminal kinase (JNK)-nuclear factor-kappa B (NF-κB)/p65 activation, and the JNK inhibition was dependent on the shizukaol C-mediated glutathione-S-transferase pi (GSTpi) expression. By further molecular docking and protein-binding analysis, we demonstrated that shizukaol C directly binds to Keap1 to induce Nrf2 nuclear translocation and upregulated GSTpi expression. Consistently, our in vivo experiment showed that shizukaol C elevated the expression level of GSTpi in carotid arteries and alleviates TMAO-induced vascular inflammation. Conclusion : Shizukaol C exerts anti-inflammatory effects in TMAO-treated VSMC by targeting Keap1 and activating Nrf2-GSTpi signaling and resultantly inhibits the downstream JNK-NF-κB p65 activation and VSMC adhesion, and alleviates TMAO-induced vascular inflammation in vivo , suggesting that shizukaol C may be a potential drug for treating TMAO-induced vascular diseases.
研究领域:
药理学
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心血管疾病
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炎症
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR MEDICINE
·
2023
·Vol. 29
·期 1
·1-19
·
IF 5.7
Han Zhiyang,Hu Haidi,Yin MingZhu,Lin Yu,Yan Yan,Han Peng,Liu Bing,Jing Bao
Background Macrophage-like transformation of vascular smooth muscle cells (VSMCs) is a risk factor of atherosclerosis (AS) progression. Transcription factor homeobox A1 (HOXA1) plays functional roles in differentiation and development. This study aims to explore the role of HOXA1 in VSMC transformation, thereby providing evidence for the potential mechanism of AS pathogenesis.Methods High fat diet (HFD)-fed apolipoprotein E knockout (ApoE−/−) mice were applied as an in vivo model to imitate AS, while 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POV-PC)-treated VSMCs were applied as an in vitro model. Recombinant adeno-associated-virus-1 (AAV-1) vectors that express short-hairpin RNAs targeting HOXA1, herein referred as AAV1-shHOXA1, were generated for the loss-of-function experiments throughout the study.Results In the aortic root of AS mice, lipid deposition was severer and HOXA1 expression was higher than the wide-type mice fed with normal diet or HFD. Silencing of HOXA1 inhibited the AS-induced weight gain, inflammatory response, serum and liver lipid metabolism disorder and atherosclerotic plaque formation. Besides, lesions from AS mice with HOXA1 knockdown showed less trans-differentiation of VSMCs to macrophage-like cells, along with a suppression of krüppel-like factor 4 (KLF4) and nuclear factor (NF)-κB RelA (p65) expression. In vitro experiments consistently confirmed that HOXA1 knockdown suppressed lipid accumulation, VSMC-to-macrophage phenotypic switch and inflammation in POV-PC-treated VSMCs. Mechanism investigations further illustrated that HOXA1 transcriptionally activated RelA and KLF4 to participate in the pathological manifestations of VSMCs.Conclusion sHOXA1 participates in AS progression by regulating VSMCs plasticity via regulation of NF-κB p65 and KLF4. HOXA1 has the potential to be a biomarker or therapeutic target for AS.
研究领域:
心血管疾病
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分子生物学
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病理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
TRENDS IN BIOTECHNOLOGY
·
2025
·
IF 14.9
Qi Li,Shuyuan Yu,Yuxuan Wang,Hui Zhao,Ziqi Gao,Huilong Du,Huayong Yang,Luqi Shen,Hongzhao Zhou
Replicating the contractile function of arterial tissues in vitro requires precise control of cell alignment within 3D structures, a challenge that existing bioprinting techniques struggle to meet. In this study, we introduce the voxel-based embedded construction for tailored orientational replication (VECTOR) method, a voxel-based approach that controls cellular orientation and collective behavior within bioprinted filaments. By fine-tuning voxel vector magnitude and using an omnidirectional printing trajectory, we achieve structural mimicry at both the macroscale and the cellular alignment level. This dual-scale approach enhances vascular smooth muscle cell (VSMC) function by regulating contractile and synthetic pathways. The VECTOR method facilitates the construction of 3D arterial structures that closely replicate natural coronary architectures, significantly improving contractility and metabolic function. Moreover, the resulting multilayered arterial models (AMs) exhibit precise responses to pharmacological stimuli, similar to native arteries. This work highlights the critical role of structural mimicry in tissue functionality and advances the replication of complex tissues in vitro .
研究领域:
生物打印
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组织工程
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生物医学工程
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细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）