Objective:Cold exposure may impair vascular function and promote cardiovascular diseases(CVDs)by causing vasoconstriction,hemodynamic changes,and sympathetic activation.Vascular aging,a key factor in CVDs,is linked to...Objective:Cold exposure may impair vascular function and promote cardiovascular diseases(CVDs)by causing vasoconstriction,hemodynamic changes,and sympathetic activation.Vascular aging,a key factor in CVDs,is linked to phenotypic switching of vascular smooth muscle cells(VSMCs),but its regulatory mechanisms are not fully understood.Materials and methods:We used aged C57BL/6 mice and D-galactose-induced senescent VSMCs to investigate the role of the E3 ligase RLIM in arterial aging.RLIM knockdown and overexpression in vivo were achieved using adeno-associated virus(AAV)vectors.Vascular aging and stiffness were assessed usingβ-galactosidase staining,pulse wave velocity(PWV)measurements,and histological staining.Proteomic profiling was conducted to identify key protein alterations associated with vascular dysfunction and to elucidate underlying mechanisms.Results:RLIM expression was significantly upregulated in the aortae of aged mice and D-galactose-induced senescent VSMCs.AAV-mediated RLIM knockdown significantly attenuated vascular aging,as evidenced by vascular ultrasound and histological assessments.Conversely,RLIM overexpression exacerbated vascular damage.Proteomic analysis revealed that RLIM knockdown in VSMCs from aged mice resulted in increased expression of smooth muscle contractile proteins and decreased levels of inflammatory markers,indicating a phenotypic shift toward a more contractile state.Conclusion:These findings identify RLIM as a key regulator of arterial aging and a promising therapeutic target for age-related cardiovascular diseases.展开更多
Background : SOX6 has been shown to play a crucial role in the development of the cardiovascular system. However, its potential role in hypertension and vascular function remains unclear. Methods : In vascular smooth ...Background : SOX6 has been shown to play a crucial role in the development of the cardiovascular system. However, its potential role in hypertension and vascular function remains unclear. Methods : In vascular smooth muscle cells(VSMCs), we employed gain-and loss-offunction approaches combined with RNA sequencing, autophagy flux assessment, and phenotype characterization. Additionally, we established a mouse model with Sox6 overexpression via adeno-associated virus 2(AAV2) to validate the findings in vivo. Results : We validated the increased expression of SOX6 in hypertension both in vitro and in vivo. Genetic silencing of Sox6 in VSMCs attenuated the phenotypic switching induced by angiotensin Ⅱ. Conversely, in vivo overexpression of Sox6 led to a significant elevation in blood pressure and promoted vascular remodeling. Mechanistically, SOX6 was shown to regulate phenotypic switching via an autophagydependent pathway. Specifically, Sox6 overexpression augmented VSMC autophagy and facilitated phenotypic switching, whereas Sox6 knockdown yielded opposite outcomes. Modulation of autophagy using 3-MA or RAPA could effectively counteract the effect mediated by SOX6. Conclusions : Our findings revealed that SOX6 regulates VSMC plasticity and elevates blood pressure by activating autophagy. Therefore, SOX6 inhibition potentially represents a novel strategy for treating hypertension and vascular remodeling.展开更多
Neuroinflammation is one of the three important pathological features in neurodegenerative diseases including Parkinson’s disease(PD).The regulation of neuroinflammation can reduce the severity of neurological damage...Neuroinflammation is one of the three important pathological features in neurodegenerative diseases including Parkinson’s disease(PD).The regulation of neuroinflammation can reduce the severity of neurological damage to alleviate diseases.Numerous studies have shown that the phenotype switch of microglia is tightly associated with the nuclear factorκB(NF-κB)-mediated inflammatory pathway.Therefore,the small interfering RNA(siRNA)therapy for downregulating the expression of NF-κB,provides a promising therapeutic strategy for Parkinson’s disease treatments.Considering the brain delivery challenges of siRNA,a sequential targeting inflammation regulation(STIR)delivery system based on poly(amino acid)s is developed to improve the therapeutic effects of Parkinson’s disease treatments.The STIR system sequentially targets the blood–brain barrier and the microglia to enhance the effective concentration of siRNA in the targeted microglia.The results demonstrate that the STIR nanoparticles can transform microglial phenotypes and regulate brain inflammation,thus achieving neuronal recovery and abnormal aggregation ofα-synuclein protein(α-syn)reduction in the treatment of Parkinson’s disease.Herein,this STIR delivery system provides a promising therapeutic platform in PD treatments and has great potential for other neurodegenerative diseases’therapies.展开更多
Background:Vascular smooth muscle cells(VSMCs)undergo a conversion from a contractile phenotype to a proliferative synthetic phenotype,contributing to the pathogenesis of cardiovascular diseases.Semaphorin 7A(SEMA7A)i...Background:Vascular smooth muscle cells(VSMCs)undergo a conversion from a contractile phenotype to a proliferative synthetic phenotype,contributing to the pathogenesis of cardiovascular diseases.Semaphorin 7A(SEMA7A)is a glycosylphosphatidylinositol-anchored membrane protein that plays an important role in vascular homeostasis by regulating endothelial cell behaviors.However,the expression and role of SEMA7A in VSMCs remain unclear.Methods:In this study,we screened for VSMC-regulating genes in publicly available datasets and analyzed the expression of SEMA7A in human coronary artery smooth muscle cells(hCASMCs)treated with platelet-derived growth factor-BB(PDGF-BB).The effects of SEMA7A overexpression and knockdown on hCASMC proliferation and migration were examined.The signaling pathways involved in the action of SEMA7A in hCASMCs were determined.Results:Bioinformatic analysis showed that SEMA7A was significantly dysregulated in VSMCs treated with oxidized low-density lipoprotein or overexpressing progerin,a pro-atherogenic gene.The PDGF-BB stimulation led to a concentration-and time-dependent induction of SEMA7A.Depletion of SEMA7A attenuated PDGF-BB-induced hCASMC proliferation and migration.Conversely,overexpression of SEMA7A enhanced hCASMC proliferation and migration.Mechanistically,SEMA7A stimulated the activation of theβ-catenin pathway and upregulated c-Myc,CCND1,and MMP7.Knockdown ofβ-catenin impaired SEMA7A-induced hCASMC proliferation and migration.Conclusions:SEMA7A triggers phenotype switching in VSMCs through theβ-catenin signaling pathway and may serve as a potential therapeutic target for cardiovascular diseases.展开更多
Hepatitis B virus(HBV)infection can cause acute hepatitis B(AHB)or chronic hepatitis B(CHB),which advances through immune tolerant(IT),immune active(IA)and inactive chronic infection(ICI)phases,leading to serious hepa...Hepatitis B virus(HBV)infection can cause acute hepatitis B(AHB)or chronic hepatitis B(CHB),which advances through immune tolerant(IT),immune active(IA)and inactive chronic infection(ICI)phases,leading to serious hepatopathy[1,2].展开更多
This study investigated the molecular mechanism of phenotypic switching of vascular smooth muscle cells(VSMCs),which play a crucial role in vascular remodeling using 9H-Carbazol-3-yl 4-aminobenzoate(CAB).CAB significa...This study investigated the molecular mechanism of phenotypic switching of vascular smooth muscle cells(VSMCs),which play a crucial role in vascular remodeling using 9H-Carbazol-3-yl 4-aminobenzoate(CAB).CAB significantly attenuated platelet-derived growth factor(PDGF)-induced VSMC proliferation and migration.CAB suppressed PDGF-induced STAT3 activation by directly binding to the SH2 domain of STAT3.Downregulation of STAT3 phosphorylation by CAB attenuated CIAPIN1/JAK2/STAT3 axis through a decrease in CIAPIN1 transcription.Furthermore,abrogated CIAPIN1 decreased KLF4-mediated VSMC dedifferentiation and increased CDKN1B-induced cell cycle arrest and MMP9 suppression.CAB inhibited intimal hyperplasia in injury-induced neointima animal models by inhibition of the CIAPIN1/JAK2/STAT3 axis.However,CIAPIN1 overexpression attenuated CAB-mediated suppression of VSMC proliferation,migration,phenotypic switching,and intimal hyperplasia.Our study clarified the molecular mechanism underlying STAT3 inhibition of VSMC phenotypic switching and vascular remodeling and identified novel active CAB.These findings demonstrated that STAT3 can be a major regulator to control CIAPIN1/JAK2/STAT3 axis that may be a therapeutic target for treating vascular proliferative diseases.展开更多
Macrophages (Mφs) play a crucial role in the pathological progression of osteoarthritis (OA) by regulating inflammation and tissue repair. Decreasing pro-inflammatory M1-Mφs and increasing anti-inflammatory M2-Mφs ...Macrophages (Mφs) play a crucial role in the pathological progression of osteoarthritis (OA) by regulating inflammation and tissue repair. Decreasing pro-inflammatory M1-Mφs and increasing anti-inflammatory M2-Mφs can alleviate OA-related inflammation and promote cartilage repair. Apoptosis is a natural process associated with tissue repair. A large number of apoptotic bodies (ABs), a type of extracellular vesicle, are produced during apoptosis, and this is associated with a reduction in inflammation. However, the functions of apoptotic bodies remain largely unknown. In this study, we investigated the role of M2-Mφs-derived apoptotic bodies (M2-ABs) in regulating the M1/M2 balance of macrophages in a mouse model of OA. Our data show that M2-ABs can be targeted for uptake by M1-Mφs, and this reprograms M1-to-M2 phenotypes within 24 h. The M2-ABs significantly ameliorated the severity of OA, alleviated the M1-mediated pro-inflammatory environment, and inhibited chondrocyte apoptosis in mice. RNA-seq revealed that M2-ABs were enriched with miR-21–5p, a microRNA that is negatively correlated with articular cartilage degeneration. Inhibiting the function of miR-21–5p in M1-Mφs significantly reduced M2-ABs-guided M1-to-M2 reprogramming following in vitro cell transfection. Together, these results suggest that M2-derived apoptotic bodies can prevent articular cartilage damage and improve gait abnormalities in OA mice by reversing the inflammatory response caused by M1 macrophages. The mechanism underlying these findings may be related to miR-21-5p-regulated inhibition of inflammatory factors. The application of M2-ABs may represent a novel cell therapy, and could provide a valuable strategy for the treatment of OA and/or chronic inflammation.展开更多
Arterial stiffness due to the vessel remodeling is closely linked to raised blood pressure,and its physiopathologic mechanism is still not fully understood.We here aimed to explore whether extracellular vesicle(EV)med...Arterial stiffness due to the vessel remodeling is closely linked to raised blood pressure,and its physiopathologic mechanism is still not fully understood.We here aimed to explore whether extracellular vesicle(EV)mediated intercellular communication between endothelium and smooth muscle cell contribute to the blood vessel remodeling under hypertension.We here revealed that the arterial endothelial cells robustly secreted EV,which in turn could be circulated and/or directly taken up by the subendothelial smooth muscle cells(SMC).Under hypertension,the EV secretion increased and the miRNA profile changed significantly mainly due to the raised mechanical force and subsequent enhanced reactive oxygen species generation.Among the miRNA cargos in the EV,miR-320d/423-5p were found increased most significantly.In vivo delivery of miR-320d/423-5p mimics via engineered EV increased their expression in arterial vessels,recapitulating the phenotype in hypertension.In contrast,therapeutic delivery of miR-320d/423-5p inhibitors via engineered EV alleviated the phenotype in spontaneous hypertension rat model.Together,we have found that the injured endothelium due to the raised mechanical force in hypertension contributes to the arterial wall remodeling via the secreted EV.Our study has not only provided novel insights on the mechanism of hypertension associated blood vessel wall remodeling,but also shed light on therapeutic intervention of hypertension associated vascular diseases.展开更多
基金the National Natural Science Foundation of China(82273919)the HMU Marshal Initiative Funding(HMUMIF-21022).
文摘Objective:Cold exposure may impair vascular function and promote cardiovascular diseases(CVDs)by causing vasoconstriction,hemodynamic changes,and sympathetic activation.Vascular aging,a key factor in CVDs,is linked to phenotypic switching of vascular smooth muscle cells(VSMCs),but its regulatory mechanisms are not fully understood.Materials and methods:We used aged C57BL/6 mice and D-galactose-induced senescent VSMCs to investigate the role of the E3 ligase RLIM in arterial aging.RLIM knockdown and overexpression in vivo were achieved using adeno-associated virus(AAV)vectors.Vascular aging and stiffness were assessed usingβ-galactosidase staining,pulse wave velocity(PWV)measurements,and histological staining.Proteomic profiling was conducted to identify key protein alterations associated with vascular dysfunction and to elucidate underlying mechanisms.Results:RLIM expression was significantly upregulated in the aortae of aged mice and D-galactose-induced senescent VSMCs.AAV-mediated RLIM knockdown significantly attenuated vascular aging,as evidenced by vascular ultrasound and histological assessments.Conversely,RLIM overexpression exacerbated vascular damage.Proteomic analysis revealed that RLIM knockdown in VSMCs from aged mice resulted in increased expression of smooth muscle contractile proteins and decreased levels of inflammatory markers,indicating a phenotypic shift toward a more contractile state.Conclusion:These findings identify RLIM as a key regulator of arterial aging and a promising therapeutic target for age-related cardiovascular diseases.
基金Beijing Nova Program,Grant/Award Number:20230484842National Natural Science Foundation of China,Grant/Award Number:82470461。
文摘Background : SOX6 has been shown to play a crucial role in the development of the cardiovascular system. However, its potential role in hypertension and vascular function remains unclear. Methods : In vascular smooth muscle cells(VSMCs), we employed gain-and loss-offunction approaches combined with RNA sequencing, autophagy flux assessment, and phenotype characterization. Additionally, we established a mouse model with Sox6 overexpression via adeno-associated virus 2(AAV2) to validate the findings in vivo. Results : We validated the increased expression of SOX6 in hypertension both in vitro and in vivo. Genetic silencing of Sox6 in VSMCs attenuated the phenotypic switching induced by angiotensin Ⅱ. Conversely, in vivo overexpression of Sox6 led to a significant elevation in blood pressure and promoted vascular remodeling. Mechanistically, SOX6 was shown to regulate phenotypic switching via an autophagydependent pathway. Specifically, Sox6 overexpression augmented VSMC autophagy and facilitated phenotypic switching, whereas Sox6 knockdown yielded opposite outcomes. Modulation of autophagy using 3-MA or RAPA could effectively counteract the effect mediated by SOX6. Conclusions : Our findings revealed that SOX6 regulates VSMC plasticity and elevates blood pressure by activating autophagy. Therefore, SOX6 inhibition potentially represents a novel strategy for treating hypertension and vascular remodeling.
基金the National Natural Science Foundation of China(Nos:22075289,21875254,31771095,and 52073287).
文摘Neuroinflammation is one of the three important pathological features in neurodegenerative diseases including Parkinson’s disease(PD).The regulation of neuroinflammation can reduce the severity of neurological damage to alleviate diseases.Numerous studies have shown that the phenotype switch of microglia is tightly associated with the nuclear factorκB(NF-κB)-mediated inflammatory pathway.Therefore,the small interfering RNA(siRNA)therapy for downregulating the expression of NF-κB,provides a promising therapeutic strategy for Parkinson’s disease treatments.Considering the brain delivery challenges of siRNA,a sequential targeting inflammation regulation(STIR)delivery system based on poly(amino acid)s is developed to improve the therapeutic effects of Parkinson’s disease treatments.The STIR system sequentially targets the blood–brain barrier and the microglia to enhance the effective concentration of siRNA in the targeted microglia.The results demonstrate that the STIR nanoparticles can transform microglial phenotypes and regulate brain inflammation,thus achieving neuronal recovery and abnormal aggregation ofα-synuclein protein(α-syn)reduction in the treatment of Parkinson’s disease.Herein,this STIR delivery system provides a promising therapeutic platform in PD treatments and has great potential for other neurodegenerative diseases’therapies.
基金supported by the Basic Research Program of Shanxi Province(Free Exploration)of China(20210302124416)Science and Technology Grant for Selected Returned Chinese Scholars of Shanxi Province of China(20220043)Four“Batches”Innovation Project of Invigorating Medical through Science and Technology of Shanxi Province of China(2022XM08).
文摘Background:Vascular smooth muscle cells(VSMCs)undergo a conversion from a contractile phenotype to a proliferative synthetic phenotype,contributing to the pathogenesis of cardiovascular diseases.Semaphorin 7A(SEMA7A)is a glycosylphosphatidylinositol-anchored membrane protein that plays an important role in vascular homeostasis by regulating endothelial cell behaviors.However,the expression and role of SEMA7A in VSMCs remain unclear.Methods:In this study,we screened for VSMC-regulating genes in publicly available datasets and analyzed the expression of SEMA7A in human coronary artery smooth muscle cells(hCASMCs)treated with platelet-derived growth factor-BB(PDGF-BB).The effects of SEMA7A overexpression and knockdown on hCASMC proliferation and migration were examined.The signaling pathways involved in the action of SEMA7A in hCASMCs were determined.Results:Bioinformatic analysis showed that SEMA7A was significantly dysregulated in VSMCs treated with oxidized low-density lipoprotein or overexpressing progerin,a pro-atherogenic gene.The PDGF-BB stimulation led to a concentration-and time-dependent induction of SEMA7A.Depletion of SEMA7A attenuated PDGF-BB-induced hCASMC proliferation and migration.Conversely,overexpression of SEMA7A enhanced hCASMC proliferation and migration.Mechanistically,SEMA7A stimulated the activation of theβ-catenin pathway and upregulated c-Myc,CCND1,and MMP7.Knockdown ofβ-catenin impaired SEMA7A-induced hCASMC proliferation and migration.Conclusions:SEMA7A triggers phenotype switching in VSMCs through theβ-catenin signaling pathway and may serve as a potential therapeutic target for cardiovascular diseases.
基金supported by the Tencent Foundation through the XPLORER PRIZEthe New Cornerstone Science Foundation。
文摘Hepatitis B virus(HBV)infection can cause acute hepatitis B(AHB)or chronic hepatitis B(CHB),which advances through immune tolerant(IT),immune active(IA)and inactive chronic infection(ICI)phases,leading to serious hepatopathy[1,2].
基金supported by a National Research Foundation(NRF)grant funded by the Korean government(MSIT,Republic of Korea)(RS-2024-00355169 to Joo-Hui Han,2022R1A2C2013309 to Chang-Seon Myung)by Woosuk University(to Joo-Hui Han,Republic of Korea).
文摘This study investigated the molecular mechanism of phenotypic switching of vascular smooth muscle cells(VSMCs),which play a crucial role in vascular remodeling using 9H-Carbazol-3-yl 4-aminobenzoate(CAB).CAB significantly attenuated platelet-derived growth factor(PDGF)-induced VSMC proliferation and migration.CAB suppressed PDGF-induced STAT3 activation by directly binding to the SH2 domain of STAT3.Downregulation of STAT3 phosphorylation by CAB attenuated CIAPIN1/JAK2/STAT3 axis through a decrease in CIAPIN1 transcription.Furthermore,abrogated CIAPIN1 decreased KLF4-mediated VSMC dedifferentiation and increased CDKN1B-induced cell cycle arrest and MMP9 suppression.CAB inhibited intimal hyperplasia in injury-induced neointima animal models by inhibition of the CIAPIN1/JAK2/STAT3 axis.However,CIAPIN1 overexpression attenuated CAB-mediated suppression of VSMC proliferation,migration,phenotypic switching,and intimal hyperplasia.Our study clarified the molecular mechanism underlying STAT3 inhibition of VSMC phenotypic switching and vascular remodeling and identified novel active CAB.These findings demonstrated that STAT3 can be a major regulator to control CIAPIN1/JAK2/STAT3 axis that may be a therapeutic target for treating vascular proliferative diseases.
基金supported by the National Natural Science Foundation of China (No. 81972069 and 82072443).
文摘Macrophages (Mφs) play a crucial role in the pathological progression of osteoarthritis (OA) by regulating inflammation and tissue repair. Decreasing pro-inflammatory M1-Mφs and increasing anti-inflammatory M2-Mφs can alleviate OA-related inflammation and promote cartilage repair. Apoptosis is a natural process associated with tissue repair. A large number of apoptotic bodies (ABs), a type of extracellular vesicle, are produced during apoptosis, and this is associated with a reduction in inflammation. However, the functions of apoptotic bodies remain largely unknown. In this study, we investigated the role of M2-Mφs-derived apoptotic bodies (M2-ABs) in regulating the M1/M2 balance of macrophages in a mouse model of OA. Our data show that M2-ABs can be targeted for uptake by M1-Mφs, and this reprograms M1-to-M2 phenotypes within 24 h. The M2-ABs significantly ameliorated the severity of OA, alleviated the M1-mediated pro-inflammatory environment, and inhibited chondrocyte apoptosis in mice. RNA-seq revealed that M2-ABs were enriched with miR-21–5p, a microRNA that is negatively correlated with articular cartilage degeneration. Inhibiting the function of miR-21–5p in M1-Mφs significantly reduced M2-ABs-guided M1-to-M2 reprogramming following in vitro cell transfection. Together, these results suggest that M2-derived apoptotic bodies can prevent articular cartilage damage and improve gait abnormalities in OA mice by reversing the inflammatory response caused by M1 macrophages. The mechanism underlying these findings may be related to miR-21-5p-regulated inhibition of inflammatory factors. The application of M2-ABs may represent a novel cell therapy, and could provide a valuable strategy for the treatment of OA and/or chronic inflammation.
基金funded by NSFC 31771507 and 81970737 to Yang GDNSFC 81871357 and 81671690 to Yuan LJ+4 种基金NSFC 81901751 to Xing CYProvincial Scientific Foundation of Shaan’Xi(2020TD-038)Innovative Development Fund of Tangdu Hospital(2018QYTS007)Clinical Trial Fund of Tangdu Hospital(2021LCYJ006)to Yuan LJfunded by MOST(2016YFA0102100).
文摘Arterial stiffness due to the vessel remodeling is closely linked to raised blood pressure,and its physiopathologic mechanism is still not fully understood.We here aimed to explore whether extracellular vesicle(EV)mediated intercellular communication between endothelium and smooth muscle cell contribute to the blood vessel remodeling under hypertension.We here revealed that the arterial endothelial cells robustly secreted EV,which in turn could be circulated and/or directly taken up by the subendothelial smooth muscle cells(SMC).Under hypertension,the EV secretion increased and the miRNA profile changed significantly mainly due to the raised mechanical force and subsequent enhanced reactive oxygen species generation.Among the miRNA cargos in the EV,miR-320d/423-5p were found increased most significantly.In vivo delivery of miR-320d/423-5p mimics via engineered EV increased their expression in arterial vessels,recapitulating the phenotype in hypertension.In contrast,therapeutic delivery of miR-320d/423-5p inhibitors via engineered EV alleviated the phenotype in spontaneous hypertension rat model.Together,we have found that the injured endothelium due to the raised mechanical force in hypertension contributes to the arterial wall remodeling via the secreted EV.Our study has not only provided novel insights on the mechanism of hypertension associated blood vessel wall remodeling,but also shed light on therapeutic intervention of hypertension associated vascular diseases.
