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1.
Rev Cardiovasc Med ; 20(3): 179-186, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31601092

RESUMO

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathyis a rare form of inherited cerebral small vessel disease associated with mutations in the high-temperature requirement serine peptidase A1 gene. As of now, only about 50 cases have been reported. In 2012, our group reported a family with a novel mutant of the high-temperature requirement serine peptidase A1 gene in China for the first time. To further explore the molecular pathogenesis of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, a recombination mouse model expressed human high-temperature requirement serine peptidase A1 gene mutant identified by our group was generated using the Donor & Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 system and termed the Mut-high-temperature requirement serine peptidase A1 geneL364P mouse model. Results show that Mut-high-temperature requirement serine peptidase A1 geneL364P mice present similar pathological characteristics to patients with cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy, suggesting that the Mut-high-temperature requirement serine peptidase A1 geneL364P mouse model was generated successfully. Moreover, apoptosis was induced in mouse brain vascular smooth muscle cells derived from Mut-high-temperature requirement serine peptidase A1 geneL364P mice. In summary, the cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy mouse model described in this study will be beneficial to demonstrate the pathological mechanism of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy and provide new therapeutic targets for clinical treatment.


Assuntos
Alopecia/genética , Encéfalo/irrigação sanguínea , Infarto Cerebral/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Leucoencefalopatias/genética , Mutação , Doenças da Coluna Vertebral/genética , Alopecia/enzimologia , Alopecia/patologia , Animais , Apoptose , Células Cultivadas , Infarto Cerebral/enzimologia , Infarto Cerebral/patologia , Predisposição Genética para Doença , Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo , Leucoencefalopatias/enzimologia , Leucoencefalopatias/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Fenótipo , Doenças da Coluna Vertebral/enzimologia , Doenças da Coluna Vertebral/patologia
2.
Arterioscler Thromb Vasc Biol ; 39(8): 1667-1681, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31092016

RESUMO

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a debilitating disease associated with progressive vascular remodeling of distal pulmonary arteries leading to elevation of pulmonary artery pressure, right ventricular hypertrophy, and death. Although presenting high levels of DNA damage that normally jeopardize their viability, pulmonary artery smooth muscle cells (PASMCs) from patients with PAH exhibit a cancer-like proproliferative and apoptosis-resistant phenotype accounting for vascular lumen obliteration. In cancer cells, overexpression of the serine/threonine-protein kinase CHK1 (checkpoint kinase 1) is exploited to counteract the excess of DNA damage insults they are exposed to. This study aimed to determine whether PAH-PASMCs have developed an orchestrated response mediated by CHK1 to overcome DNA damage, allowing cell survival and proliferation. Approach and Results: We demonstrated that CHK1 expression is markedly increased in isolated PASMCs and distal PAs from patients with PAH compared with controls, as well as in multiple complementary animal models recapitulating the disease, including monocrotaline rats and the simian immunodeficiency virus-infected macaques. Using a pharmacological and molecular loss of function approach, we showed that CHK1 promotes PAH-PASMCs proliferation and resistance to apoptosis. In addition, we found that inhibition of CHK1 induces downregulation of the DNA repair protein RAD 51 and severe DNA damage. In vivo, we provided evidence that pharmacological inhibition of CHK1 significantly reduces vascular remodeling and improves hemodynamic parameters in 2 experimental rat models of PAH. CONCLUSIONS: Our results show that CHK1 exerts a proproliferative function in PAH-PASMCs by mitigating DNA damage and suggest that CHK1 inhibition may, therefore, represent an attractive therapeutic option for patients with PAH.


Assuntos
Quinase 1 do Ponto de Checagem/antagonistas & inibidores , /tratamento farmacológico , Animais , Apoptose , Proteínas Mutadas de Ataxia Telangiectasia/fisiologia , Células Cultivadas , Quinase 1 do Ponto de Checagem/fisiologia , Dano ao DNA , Modelos Animais de Doenças , Humanos , Masculino , MicroRNAs/fisiologia , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/fisiologia , Ratos , Ratos Sprague-Dawley
3.
Nutr Metab Cardiovasc Dis ; 29(6): 621-632, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31005375

RESUMO

BACKGROUND AND AIMS: The vascular remodeling plays a crucial role in pathogenesis of diabetic cardiovascular complications. In this study, we intended to explore the effects and potential mechanisms of microRNA-24 (miR-24) on vascular remodeling under diabetic conditions. METHODS AND RESULTS: MiR-24 recombinant adenovirus (Ad-miR-24-GFP) was used to induce miR-24 overexpression either in carotid arteries or high glucose (HG)-induced vascular smooth muscle cells (VSMCs). Cell proliferation was analyzed using CCK-8 method. Cell migration was examined using wound-healing and transwell assay. mRNA and protein expressions of critical factors were, respectively, measured by real-time PCR and western blot as follows: qRT-PCR for the levels of miR-24, PIK3R1; western blot for the protein levels of PI3K (p85α), Akt, p-Akt, mTOR, p-mTOR, 4E-BP1, p-4E-BP1, p70s6k, p-p70s6k, MMP 2, MMP 9, collagen Ⅰ, as well as collagen Ⅲ. Carotid arteries in diabetic rats suffered balloon injury were harvested and examined by HE, immunohistochemical and Masson trichrome staining. The expression of miR-24 was decreased in HG-stimulated VSMCs and balloon-injured carotid arteries of diabetic rats, accompanied by increased mRNA expression of PIK3R1. The up-regulation of miR-24 suppressed VSMCs proliferation, migration, collagen deposition not only induced by HG in vitro, but also in balloon-injured diabetic rats, which were related to inactivation of PI3K/Akt signaling pathway. CONCLUSION: The up-regulation of miR-24 significantly attenuated vascular remodeling both in balloon-injured diabetic rats and HG-stimulated VSMCs via suppression of proliferation, migration and collagen deposition by acting on PIK3R1 gene that modulated the PI3K/Akt/mTOR axes.


Assuntos
Lesões das Artérias Carótidas/enzimologia , Diabetes Mellitus Experimental/enzimologia , MicroRNAs/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Remodelação Vascular , Animais , Artérias Carótidas/enzimologia , Artérias Carótidas/patologia , Lesões das Artérias Carótidas/genética , Lesões das Artérias Carótidas/patologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Colágenos Fibrilares/metabolismo , Masculino , MicroRNAs/genética , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Neointima , Ratos Sprague-Dawley , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
4.
J Vasc Surg ; 69(5): 1581-1589.e1, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31010523

RESUMO

OBJECTIVE: Current drug-eluting stent (DES) treatment is promising, but it still has the drawback of in-stent restenosis, which remains a clinically relevant problem. Efforts should be made to discover new signaling molecules and novel potential targets for the prevention of arterial restenosis. In this study, we fabricated a novel DES targeting the RhoA pathway and further examined this promising strategy in vitro and in a rabbit carotid model. METHODS: Active RhoA expression is correlated with the synthetic smooth muscle phenotype, and the RhoA inhibitor rhosin suppresses this phenotypic modulation at both transcriptional and translational levels. We further demonstrated that the RhoA inhibitor rhosin might act through the YAP pathway in smooth muscle cell phenotype modulation by a gain-of-function assay. Moreover, we fabricated a RhoA inhibitor-eluting stent and tested it in a rabbit carotid model. RESULTS: Compared with a bare-metal stent, the RhoA inhibitor-eluting stent significantly attenuated neointimal formation at 6 months. However, overexpression of YAP by lentivirus blocked the antirestenosis effect of the RhoA inhibitor-eluting stent and repressed smooth muscle-specific genes. CONCLUSIONS: RhoA inhibitor-eluting stents attenuate neointimal formation through inhibition of the YAP signaling pathway. This novel DES may represent a potential strategy for the treatment of in-stent restenosis.


Assuntos
Angioplastia com Balão/instrumentação , Proliferação de Células/efeitos dos fármacos , Stents Farmacológicos , Inibidores Enzimáticos/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Compostos Orgânicos/farmacologia , Proteínas Proto-Oncogênicas c-yes/metabolismo , Proteínas rho de Ligação ao GTP/antagonistas & inibidores , Angioplastia com Balão/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/enzimologia , Artérias Carótidas/patologia , Células Cultivadas , Constrição Patológica , Masculino , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Neointima , Proteínas Proto-Oncogênicas c-yes/genética , Coelhos , Ratos , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Proteínas rho de Ligação ao GTP/metabolismo
5.
Microvasc Res ; 124: 43-50, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30853343

RESUMO

Pulmonary arterial hypertension (PAH) is a devastating and fatal vascular disease for which currently there is no satisfying therapy available. Excessive cell proliferation of pulmonary arterial smooth muscle cells (PASMCs) contributes significantly to PAH pathogenesis. In this study, we found that miR-205-5p was lowly expressed in hypoxia-induced PAH mouse model and hypoxia-treated PASMCs. Restoration of miR-205-5p suppressed PASMCs proliferation. In contrast, molecule interacting with CasL 2 (MICAL2) was highly expressed in hypoxia-induced PAH mouse model and hypoxia-treated PASMCs. Overexpression of MICAL2 promoted cell proliferation. Furthermore, miR-205-5p inhibited MICAL2 expression levels by targeting the MICAL2 3' untranslated region. In addition, MICAL2 activated ERK1/2 signaling in PASMCs and ERK1/2 inhibitor blocked MICAL2-mediated-promotion effect on PASMCs proliferation. These results demonstrated that miR-205-5p suppressed PASMCs proliferation by targeting MICAL2, which activated ERK1/2 signaling. Therefore, miR-205-5p/MICAL2/Erk1/2 may serve as an ideal therapeutic target to PAH treatment.


Assuntos
Proliferação de Células , Proteínas do Citoesqueleto/metabolismo , Hipertensão Pulmonar/enzimologia , MicroRNAs/metabolismo , Proteínas dos Microfilamentos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Oxirredutases/metabolismo , Animais , Células Cultivadas , Proteínas do Citoesqueleto/genética , Modelos Animais de Doenças , Humanos , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/patologia , Hipóxia/complicações , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Proteínas dos Microfilamentos/genética , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Oxirredutases/genética , Artéria Pulmonar/enzimologia , Artéria Pulmonar/patologia , Transdução de Sinais , Remodelação Vascular
6.
Vascul Pharmacol ; 116: 16-23, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30822571

RESUMO

Long noncoding RNA-steroid receptor RNA activator (LncRNA-SRA) is transcribed from a class of noncoding genes, and plays a critical role in regulating cell proliferation. However, the effect of lncRNA-SRA remains unclear in vascular proliferative diseases. In the present study, we overexpressed lncRNA-SRA in vitro, then investigated the biological consequences. A vascular damage mice model was constructed by performing femoral artery wire injury. LncRNA-SRA was overexpressed in the injured arteries, and significantly promoted the expression of ki67, thereby caused an overall increase in neointima formation. LncRNA-SRA overexpression led to the proliferation and migration of vascular smooth muscle cells (VSMCs). By stimulating the phosphorylation of MEK, ERK and CREB (cyclic nucleotide responsive element binding protein), lncRNA-SRA promoted VSMC proliferation. Meanwhile, these effects were blocked by the MEK inhibitor U0126. Therefore, lncRNA-SRA promoted VSMC proliferation by activating the MEK-ERK-CREB pathway. LncRNA-SRA could be a promising therapeutic target in vascular diseases characterized by neointimal hyperplasia.


Assuntos
Proliferação de Células , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Neointima , RNA Longo não Codificante/metabolismo , Lesões do Sistema Vascular/enzimologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Artéria Femoral/enzimologia , Artéria Femoral/lesões , Artéria Femoral/patologia , Hiperplasia , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/lesões , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Fosforilação , RNA Longo não Codificante/genética , Transdução de Sinais , Lesões do Sistema Vascular/genética , Lesões do Sistema Vascular/patologia
7.
Cell Physiol Biochem ; 52(1): 76-93, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30790506

RESUMO

BACKGROUND/AIMS: Protein kinase C (PKC)- and RhoA/Rho-associated kinase (ROCK) play important roles in arterial sustained contraction. Although depolarization-elicited RhoA/ROCK activation is accepted, the role of PKC in depolarized vascular smooth muscle cells (VSMCs) is a subject of controversy. Our aim was to study the role of PKC in arterial contraction and its interaction with RhoA/ROCK. METHODS: Mass spectrometry was used to identify the PKC isoenzymes. PKCα levels and RhoA activity were analyzed by western blot and G-LISA, respectively, and isometric force was measured in arterial rings. RESULTS: In depolarized VSMCs RhoA and PKCα were translocated to the plasma membrane, where they colocalize and coimmunoprecipitate. Interestingly, depolarization-induced RhoA activation was downregulated by PKCα, effect reverted by PKCα inhibition. Phorbol 12,13-dibutyrate (PDBu) induced the translocation of PKCα to the plasma membrane, increased the level of RhoA in the cytosol and reduced RhoA/ROCK activity. These effects were reverted when PKC was inhibited. Pharmacological or siRNA inhibition of PKCα synergistically potentiated the vasorelaxant effect of RhoA/ROCK inhibition. CONCLUSION: The present study provides the first evidence that RhoA activity is downregulated by PKCα in depolarized and PDBu treated freshly isolated VSMCs and arteries, with an important physiological role on arterial contractility.


Assuntos
Membrana Celular/enzimologia , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Proteína Quinase C-alfa/metabolismo , Vasodilatação , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Masculino , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , Dibutirato de 12,13-Forbol/farmacologia , Transporte Proteico/efeitos dos fármacos , Ratos , Ratos Wistar , Quinases Associadas a rho/metabolismo
8.
Arterioscler Thromb Vasc Biol ; 39(3): e91-e105, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30651001

RESUMO

Objective- Vascular smooth muscle cells (VSMCs) phenotype modulation is critical for the resolution of vascular injury. Genetic and pharmacological inhibition of PI3Kγ (phosphoinositide 3-kinase γ) exerts anti-inflammatory and protective effects in multiple cardiovascular diseases. This study investigated the role of PI3Kγ and its downstream effector molecules in the regulation of VSMC phenotypic modulation and neointimal formation in response to vascular injury. Approach and Results- Increased expression of PI3Kγ was found in injured vessel wall as well in cultured, serum-activated wild-type VSMCs, accompanied by a reduction in the expression of calponin and SM22α, 2 differentiation markers of VSMCs. However, the injury-induced downregulation of calponin and SM22α was profoundly attenuated in PI3Kγ-/- mice. Pharmacological inhibition and short hairpin RNA knockdown of PI3Kγ (PI3Kγ-KD) markedly attenuated YAP (Yes-associated protein) expression and CREB (cyclic AMP-response element binding protein) activation but improved the downregulation of differentiation genes in cultured VSMCs accompanied by reduced cell proliferation and migration. Mechanistically, activated CREB upregulated YAP transcriptional expression through binding to its promoter. Ectopic expression of YAP strikingly repressed the expression of differentiation genes even in PI3Kγ-KD VSMCs. Moreover, established carotid artery ligation and chimeric mice models demonstrate that deletion of PI3Kγ in naïve PI3Kγ-/- mice as well as in chimeric mice lacking PI3Kγ either in bone marrow or vascular wall significantly reduced neointimal formation after injury. Conclusions- PI3Kγ controls phenotypic modulation of VSMCs by regulating transcription factor CREB activation and YAP expression. Modulating PI3Kγ signaling on local vascular wall may represent a new therapeutic approach to treat proliferative vascular disease.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Proteínas de Ciclo Celular/fisiologia , Classe Ib de Fosfatidilinositol 3-Quinase/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/fisiologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Neointima/fisiopatologia , Transdução de Sinais/fisiologia , Animais , Artéria Carótida Primitiva , Movimento Celular , Células Cultivadas , Classe Ib de Fosfatidilinositol 3-Quinase/deficiência , Classe Ib de Fosfatidilinositol 3-Quinase/genética , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Ligadura , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/patologia , Fenótipo , Interferência de RNA , RNA Interferente Pequeno/genética , Quimera por Radiação , Remodelação Vascular
9.
Ann Vasc Surg ; 57: 201-209, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30684618

RESUMO

BACKGROUND: Intimal hyperplasia (IH) is the most common indicator for secondary intervention in peripheral vascular disease. Matrix metalloproteinases (MMPs) play a role in IH development due to their degradation of the extracellular matrix. Doxycycline (Doxy), a member of the tetracycline family of antibiotics, is a potent MMP inhibitor. We have previously shown that Doxy inhibits MMP activity and vascular smooth muscle cell migration in vitro. We hypothesized that Doxy would decrease MMP activity in vivo and inhibit the development of IH in a rodent model of vascular injury. METHODS AND RESULTS: Doxy (400 mg/pellet) was delivered by a slow-release pellet implanted 3 days prior to or at the time of balloon angioplasty (BA) of the common carotid artery in female rats. At 14 days post-BA, intima-to-media (I:M) ratios were 0.77 ± 0.21 and 1.04 ± 0.32 in the Doxy treated groups, respectively, compared to 1.25 ± 0.26 in the control group (P = not significant; n = 3). Additionally, the tested dose of Doxy in either group had no inhibitory effect on membrane type 1-MMP or MMP-2 tissue levels, as measured by immunohistochemistry, or on systemic levels of MMP, as measured by total MMP serum levels using enzyme-linked immunosorbent assay. At 14 days post-BA, VSMC proliferation in the injured artery was increased to Doxy treatment prior to and at the time of surgery (23.5 ± 3.4 and 27.2 ± 3.9%, respectively), compared to control (11.4 ± 0.4%; n = 3), as measured by proliferating cellular nuclear antigen immunostaining. CONCLUSIONS: In our in vivo model of vascular injury, systemic Doxy administration prior to or at the time of vascular injury does not significantly hinder the progression of IH development. Additional doses and routes of administration could be examined in order to correlate therapeutic serum levels of Doxy with effective MMP inhibition in serum and arterial tissue. However, alternative drug delivery systems are needed in order to optimize therapeutic administration of targeted MMP inhibitors for the prevention of IH development.


Assuntos
Angioplastia com Balão/efeitos adversos , Fármacos Cardiovasculares/administração & dosagem , Lesões das Artérias Carótidas/tratamento farmacológico , Doxiciclina/administração & dosagem , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Neointima , Animais , Lesões das Artérias Carótidas/sangue , Lesões das Artérias Carótidas/enzimologia , Lesões das Artérias Carótidas/patologia , Artéria Carótida Primitiva/efeitos dos fármacos , Artéria Carótida Primitiva/enzimologia , Artéria Carótida Primitiva/patologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Hiperplasia , Metaloproteinase 14 da Matriz/sangue , Metaloproteinase 2 da Matriz/sangue , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/lesões , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Ratos Sprague-Dawley
10.
Am J Physiol Lung Cell Mol Physiol ; 316(1): L175-L186, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30358439

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fibroproliferative lung disease, and fibroblast-myofibroblast differentiation (FMD) is thought to be a key event in the pathogenesis of IPF. Histone deacetylase-8 (HDAC8) has been shown to associate with α-smooth muscle actin (α-SMA; a marker of FMD) and regulates cell contractility in vascular smooth muscle cells. However, the role of HDAC8 in FMD or pulmonary fibrosis has never been reported. This study investigated the role of HDAC8 in pulmonary fibrosis with a focus on FMD. We observed that HDAC8 expression was increased in IPF lung tissue as well as transforming growth factor (TGF)ß1-treated normal human lung fibroblasts (NHLFs). Immunoprecipitation experiments revealed that HDAC8 was associated with α-SMA in TGFß1-treated NHLFs. HDAC8 inhibition with NCC170 (HDAC8-selective inhibitor) repressed TGFß1-induced fibroblast contraction and α-SMA protein expression in NHLFs cultured in collagen gels. HDAC8 inhibition with HDAC8 siRNA also repressed TGFß1-induced expression of profibrotic molecules such as fibronectin and increased expression of antifibrotic molecules such as peroxisome proliferator-activated receptor-γ (PPARγ). Chromatin immunoprecipitation quantitative PCR using an antibody against H3K27ac (histone H3 acetylated at lysine 27; a known HDAC8 substrate and a marker for active enhancers) suggested that HDAC8 inhibition with NCC170 ameliorated TGFß1-induced loss of H3K27ac at the PPARγ gene enhancer. Furthermore, NCC170 treatment significantly decreased fibrosis measured by Ashcroft score as well as expression of type 1 collagen and fibronectin in bleomycin-treated mouse lungs. These data suggest that HDAC8 contributes to pulmonary fibrosis and that there is a therapeutic potential for HDAC8 inhibitors to treat IPF as well as other fibrotic lung diseases.


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Miofibroblastos/enzimologia , Proteínas Repressoras/antagonistas & inibidores , Acetilação/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Histona Desacetilases/biossíntese , Histonas/metabolismo , Humanos , Fibrose Pulmonar Idiopática/enzimologia , Fibrose Pulmonar Idiopática/patologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Miofibroblastos/patologia , PPAR gama/metabolismo , Proteínas Repressoras/biossíntese , Fator de Crescimento Transformador beta1/metabolismo
11.
Toxicol Appl Pharmacol ; 364: 45-54, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30529164

RESUMO

Defective autophagy in vascular smooth muscle cells (VSMCs) is the principal cause of atherosclerosis. This study aimed to investigate the effect of astragaloside IV (AS-IV) on VSMCs autophagy. In vivo, ApoE-/- mice were fed with high-fat diet ad libitum for eight weeks, with or without AS-IV (25 mg/kg, daily). In vitro, human VSMCs were cultured and treated with ß-Glycerophosphate (10 mmol/L) and AS-IV (50 µg/ml). VSMCs autophagy, mineralization, expression of p-ERK1/2, p-mTOR, and autophagy-related proteins (LC3 II/I, p62, and Beclin 1) were detected. Increased autophagy and mineralization was observed in VSMCs in thoracic aorta of mice and in in vitro VSMCs model of atherosclerosis. AS-IV administration attenuated the autophagy and mineralization in VSMCs. Reverse expression profiles of H19 and DUSP5 were observed. AS-IV inhibited DUSP5 and autophagy-related proteins and increased expression of H19, level of p-ERK1/2 and p-mTOR. Further, autophagy and mineralization level in VSMCs were in line with DUSP5 expression level, but in contrast to H19, p-ERK1/2, and p-mTOR profiles. We demonstrated that AS-IV could attenuate autophagy and mineralization of VSMCs in atherosclerosis, which may be associated with H19 overexpression and DUSP5 inhibition.


Assuntos
Aterosclerose/prevenção & controle , Autofagia/efeitos dos fármacos , Fosfatases de Especificidade Dupla/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , RNA Longo não Codificante/metabolismo , Saponinas/farmacologia , Triterpenos/farmacologia , Calcificação Vascular/prevenção & controle , Animais , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Proteínas Relacionadas à Autofagia/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Fosfatases de Especificidade Dupla/genética , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Fosforilação , Placa Aterosclerótica , RNA Longo não Codificante/genética , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Calcificação Vascular/enzimologia , Calcificação Vascular/genética , Calcificação Vascular/patologia
12.
Nat Commun ; 9(1): 5022, 2018 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-30479344

RESUMO

Abdominal aortic aneurysms (AAA) are characterized by extensive extracellular matrix (ECM) fragmentation and inflammation. However, the mechanisms by which these events are coupled thereby fueling focal vascular damage are undefined. Here we report through single-cell RNA-sequencing of diseased aorta that the neuronal guidance cue netrin-1 can act at the interface of macrophage-driven injury and ECM degradation. Netrin-1 expression peaks in human and murine aneurysmal macrophages. Targeted deletion of netrin-1 in macrophages protects mice from developing AAA. Through its receptor neogenin-1, netrin-1 induces a robust intracellular calcium flux necessary for the transcriptional regulation and persistent catalytic activation of matrix metalloproteinase-3 (MMP3) by vascular smooth muscle cells. Deficiency in MMP3 reduces ECM damage and the susceptibility of mice to develop AAA. Here, we establish netrin-1 as a major signal that mediates the dynamic crosstalk between inflammation and chronic erosion of the ECM in AAA.


Assuntos
Aneurisma da Aorta Abdominal/metabolismo , Macrófagos/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Netrina-1/metabolismo , Animais , Cálcio/metabolismo , Deleção de Genes , Hematopoese , Humanos , Proteínas de Membrana , Camundongos Endogâmicos C57BL , Netrina-1/deficiência
13.
Biomed Res Int ; 2018: 7902081, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30386795

RESUMO

Coronary artery disease (CAD) and stroke are the most common and serious long-term complications of hypertension. Acetylsalicylic acid (ASA) significantly reduces their incidence and cardiovascular mortality. The RAAS activation plays an important role in pathogenesis of CVD, resulting in increased vascular resistance, proliferation of vascular-smooth-muscle-cells, and cardiac hypertrophy. Drugs acting on the renin-angiotensin-aldosterone system (RAAS) are demonstrated to reduce cardiovascular events in population with cardiovascular disease (CVD). The cyclooxygenase inhibitors limit the beneficial effect of RAAS-inhibitors, which in turn may be important in subjects with hypertension, CAD, and congestive heart failure. These observations apply to most of nonsteroidal anti-inflammatory drugs and ASA at high doses. Nevertheless, there is no strong evidence confirming presence of similar effects of cardioprotective ASA doses. The benefit of combined therapy with low-doses of ASA is-in some cases-significantly higher than that of monotherapy. So far, the significance of ASA in optimizing the pharmacotherapy remains not fully established. A better understanding of its influence on the particular CVD should contribute to more precise identification of patients in whom benefits of ASA outweigh the complication risk. This brief review summarizes the data regarding usefulness and safety of the ASA combination with drugs acting directly on the RAAS.


Assuntos
Aspirina/uso terapêutico , Cardiotônicos/uso terapêutico , Doenças Cardiovasculares , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/prevenção & controle , Humanos
14.
Arterioscler Thromb Vasc Biol ; 38(10): 2295-2305, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30354204

RESUMO

Objective- Signaling that activates NFκB (nuclear factor κB) in smooth muscle cells (SMCs) is integral to atherosclerosis and involves reversible ubiquitination that activates proteins downstream of proatherogenic receptors. Deubiquitination of these proteins is mediated by USP20 (ubiquitin-specific protease 20), among other deubiquitinases. We sought to determine whether USP20 activity in SMCs decreases atherosclerosis. Approach and Results- To address this question, we used male Ldlr-/- mice without (control) or with SMC-specific expression of murine USP20 (SMC-USP20-transgenic) or its dominant-negative (DN; C154S/H643Q) mutant (SMC-DN-USP20-transgenic). Before the appearance of intimal macrophages, NFκB activation in aortic medial SMCs was greater in SMC-DN-USP20-transgenic than in control mice. After 16 weeks on a Western diet, SMC-DN-USP20-transgenic mice had 46% greater brachiocephalic artery atheroma area than control mice. Congruently, aortic atherosclerosis assessed en face was 21% greater than control in SMC-DN-USP20-transgenic mice and 13% less than control in SMC-USP20-transgenic mice. In response to TNF (tumor necrosis factor), SMCs from SMC-DN-USP20-transgenic mice showed ≈3-fold greater NFκB activation than control SMCs. Silencing USP20 in SMCs with siRNA (small interfering RNA) augmented NFκB activation by ≈50% in response to either TNF or IL-1ß (interleukin-1ß). Coimmunoprecipitation experiments revealed that USP20 associates with several components of the TNFR1 (TNF receptor-1) signaling pathway, including RIPK1 (receptor-interacting protein kinase 1), a critical checkpoint in TNF-induced NFκB activation and inflammation. TNF evoked ≈2-fold more RIPK1 ubiquitination in SMC-DN-USP20-transgenic than in control SMCs, and RIPK1 was deubiquitinated by purified USP20 in vitro. Conclusions- USP20 attenuates TNF- and IL-1ß-evoked atherogenic signaling in SMCs, by deubiquitinating RIPK1, among other signaling intermediates.


Assuntos
Aortite/prevenção & controle , Aterosclerose/prevenção & controle , Endopeptidases/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Fator de Necrose Tumoral alfa/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/enzimologia , Aorta/patologia , Aortite/enzimologia , Aortite/genética , Aortite/patologia , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Células Cultivadas , Modelos Animais de Doenças , Endopeptidases/genética , Feminino , Hiperplasia , Interleucina-1beta/farmacologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , NF-kappa B/metabolismo , Neointima , Placa Aterosclerótica , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Receptores de LDL , Receptores Tipo I de Fatores de Necrose Tumoral/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ubiquitinação
15.
Arterioscler Thromb Vasc Biol ; 38(10): 2382-2395, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30354214

RESUMO

Objective- Vascular calcification is a major risk factor for rupture of atherosclerotic plaques. High expression of BMP2 (bone morphogenetic protein 2) in lesions suggests its importance in vascular calcification during atherosclerosis. Teniposide is a Topo II (DNA topoisomerase II) inhibitor and is used for cancer treatment. Previously, we reported that teniposide activated macrophage ABCA1 (ATP-binding cassette transporter A1) expression and free cholesterol efflux indicating Topo II inhibitors may demonstrate antiatherogenic properties. Herein, we investigated the effects of teniposide on the development of atherosclerosis and vascular calcification in apoE-/- (apoE deficient) mice. Approach and Results- apoE-/- mice were fed high-fat diet containing teniposide for 16 weeks, or prefed high-fat diet for 12 weeks followed by high-fat diet containing teniposide for 4 weeks. Atherosclerosis and vascular calcification were determined. Human aortic smooth muscle cells were used to determine the mechanisms for teniposide-inhibited vascular calcification. Teniposide reduced atherosclerotic lesions. It also substantially reduced vascular calcification without affecting bone structure. Mechanistically, teniposide reduced vascular calcification by inactivating BMP2/(pi-Smad1/5/8 [mothers against decapentaplegic homolog 1, 5, and 8])/RUNX2 (runt-related transcription factor 2) axis in a p53-dependent manner. Furthermore, activated miR-203-3p by teniposide functioned as a link between activated p53 expression and inhibited BMP2 expression in inhibition of calcification. Conclusions- Our study demonstrates that teniposide reduces vascular calcification by regulating p53-(miR-203-3p)-BMP2 signaling pathway, which contributes to the antiatherogenic properties of Topo II inhibitors.


Assuntos
Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Teniposídeo/farmacologia , Inibidores da Topoisomerase II/farmacologia , Calcificação Vascular/prevenção & controle , Regiões 3' não Traduzidas , Fosfatase Alcalina/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/enzimologia , Aorta/patologia , Doenças da Aorta/enzimologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Proteína Morfogenética Óssea 2/genética , Proteína Morfogenética Óssea 2/metabolismo , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/genética , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Camundongos Knockout para ApoE , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Calcificação Vascular/enzimologia , Calcificação Vascular/genética , Calcificação Vascular/patologia
16.
Arterioscler Thromb Vasc Biol ; 38(10): 2423-2434, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30354218

RESUMO

Objective- Actin cytoskeleton assembly and organization, as a result of focal adhesion (FA) formation during cell adhesion, are dependent on reactive oxygen species and the cellular redox environment. Poldip2 (polymerase δ-interacting protein 2), a novel regulator of NOX4 (NADPH oxidase 4), plays a significant role in reactive oxygen species production and cytoskeletal remodeling. Thus, we hypothesized that endogenous reactive oxygen species derived from Poldip2/NOX4 contribute to redox regulation of actin and cytoskeleton assembly during integrin-mediated cell adhesion. Approach and Results- Using vascular smooth muscle cells, we verified that hydrogen peroxide (H2O2) levels increase during integrin-mediated cell attachment as a result of activation of NOX4. Filamentous actin (F-actin) was oxidized by sulfenylation during cell attachment, with a peak at 3 hours (0.80±0.04 versus 0.08±0.13 arbitrary units at time zero), which was enhanced by overexpression of Poldip2. Depletion of Poldip2 or NOX4 using siRNA, or scavenging of endogenous H2O2 with catalase, inhibited F-actin oxidation by 78±26%, 99±1%, and 98±1%, respectively. To determine the consequence of F-actin oxidation, we examined the binding of F-actin to vinculin, a protein involved in FA complexes that regulates FA maturation. Vinculin binding during cell adhesion as well as migration capacity were inhibited after transfection with actin containing 2 oxidation-resistant point mutations (C272A and C374A). Silencing of Poldip2 or NOX4 also impaired actin-vinculin interaction, which disturbed maturation of FAs and inhibited cell migration. Conclusions- These results suggest that integrin engagement during cell attachment activates Poldip2/Nox4 to oxidize actin, which modulates FA assembly.


Assuntos
Citoesqueleto de Actina/enzimologia , Proteínas de Transporte/metabolismo , Adesão Celular , Integrinas/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , NADPH Oxidase 4/metabolismo , Proteínas Nucleares/metabolismo , Vinculina/metabolismo , Citoesqueleto de Actina/genética , Animais , Proteínas de Transporte/genética , Movimento Celular , Células Cultivadas , Humanos , Peróxido de Hidrogênio/metabolismo , Músculo Liso Vascular/ultraestrutura , Miócitos de Músculo Liso/ultraestrutura , NADPH Oxidase 4/genética , Proteínas Nucleares/genética , Oxirredução , Ratos , Transdução de Sinais
17.
Nat Commun ; 9(1): 3850, 2018 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-30242159

RESUMO

The molecular mechanisms underlying the metabolic shift toward increased glycolysis observed in pulmonary artery smooth muscle cells (PASMC) during the pathogenesis of pulmonary arterial hypertension (PAH) are not fully understood. Here we show that the glycolytic enzyme α-enolase (ENO1) regulates the metabolic reprogramming and malignant phenotype of PASMC. We show that ENO1 levels are elevated in patients with associated PAH and in animal models of hypoxic pulmonary hypertension (HPH). The silencing or inhibition of ENO1 decreases PASMC proliferation and de-differentiation, and induces PASMC apoptosis, whereas the overexpression of ENO1 promotes a synthetic, de- differentiated, and apoptotic-resistant phenotype via the AMPK-Akt pathway. The suppression of ENO1 prevents the hypoxia-induced metabolic shift from mitochondrial respiration to glycolysis in PASMC. Finally, we find that pharmacological inhibition of ENO1 reverses HPH in mice and rats, suggesting ENO1 as a regulator of pathogenic metabolic reprogramming in HPH.


Assuntos
Hipertensão Pulmonar/etiologia , Miócitos de Músculo Liso/enzimologia , Fosfopiruvato Hidratase/metabolismo , Adenilato Quinase/metabolismo , Animais , Apoptose , Diferenciação Celular , Respiração Celular , Modelos Animais de Doenças , Glicólise , Humanos , Hipertensão Pulmonar/enzimologia , Camundongos , Fenótipo , Fosfopiruvato Hidratase/antagonistas & inibidores , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/metabolismo , Artéria Pulmonar/enzimologia , Ratos
18.
Bull Exp Biol Med ; 165(5): 602-605, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30225707

RESUMO

LPS has an inhibitory effect on contractile activity of bovine mesenteric lymphatic vessels and nodes and causes a pronounced decrease in the tone and phase contractions. The selective inhibitor of inducible NO synthase, 1400W, and cyclooxygenase-2 selective inhibitor, dynastat, significantly attenuated the inhibitory effect of LPS. Dexamethasone interferes with the inhibitory effect of LPS on bovine lymphatic vessels and nodes. It was concluded that LPS stimulates expression of inducible NO synthase and cyclooxygenase-2 in endothelial and smooth muscle cells of lymphatic vessels and nodes. Dexamethasone has a pronounced protective effect on the contractile function of lymphatic vessels and nodes affected by LPS and suppresses the expression of inducible NO synthase and cyclooxygenase-2.


Assuntos
Anti-Inflamatórios/farmacologia , Dexametasona/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Linfonodos/efeitos dos fármacos , Vasos Linfáticos/efeitos dos fármacos , Amidinas/farmacologia , Animais , Benzilaminas/farmacologia , Bovinos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/enzimologia , Expressão Gênica , Isoxazóis/farmacologia , Lipopolissacarídeos/farmacologia , Linfonodos/citologia , Linfonodos/enzimologia , Vasos Linfáticos/citologia , Vasos Linfáticos/enzimologia , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/citologia , Músculo Liso/efeitos dos fármacos , Músculo Liso/enzimologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/enzimologia , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Técnicas de Cultura de Tecidos
19.
J Biol Chem ; 293(43): 16677-16686, 2018 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-30185619

RESUMO

Contractile force development of smooth muscle is controlled by balanced kinase and phosphatase activities toward the myosin regulatory light chain (RLC). Numerous biochemical and pharmacological studies have investigated the specificity and regulatory activity of smooth muscle myosin light-chain phosphatase (MLCP) bound to myosin filaments and comprised of the regulatory myosin phosphatase target subunit 1 (MYPT1) and catalytic protein phosphatase 1cß (PP1cß) subunits. Recent physiological and biochemical evidence obtained with smooth muscle tissues from a conditional MYPT1 knockout suggests that a soluble, MYPT1-unbound form of PP1cß may additionally contribute to myosin RLC dephosphorylation and relaxation of smooth muscle. Using a combination of isoelectric focusing and isoform-specific immunoblotting, we found here that more than 90% of the total PP1c in mouse smooth muscles is the ß isoform. Moreover, conditional knockout of PP1cα or PP1cγ in adult smooth muscles did not result in an apparent phenotype in mice up to 6 months of age and did not affect smooth muscle contractions ex vivo In contrast, smooth muscle-specific conditional PP1cß knockout decreased contractile force development in bladder, ileal, and aortic tissues and reduced mouse survival. Bladder smooth muscle tissue from WT mice was selectively permeabilized to remove soluble PP1cß to measure contributions of total (α-toxin treatment) and myosin-bound (Triton X-100 treatment) phosphatase activities toward phosphorylated RLC in myofilaments. Triton X-100 reduced PP1cß content by 60% and the rate of RLC dephosphorylation by 2-fold. These results are consistent with the selective dephosphorylation of RLC by both MYPT1-bound and -unbound PP1cß forms in smooth muscle.


Assuntos
Músculo Liso/enzimologia , Proteína Fosfatase 1/metabolismo , Animais , Íleo/enzimologia , Íleo/fisiologia , Isoenzimas/genética , Isoenzimas/metabolismo , Masculino , Camundongos , Camundongos Knockout , Contração Muscular , Músculo Liso/fisiologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/fisiologia , Fosforilação , Proteína Fosfatase 1/genética , Bexiga Urinária/enzimologia , Bexiga Urinária/fisiologia
20.
Atherosclerosis ; 277: 98-107, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30193190

RESUMO

BACKGROUND AND AIMS: Collagen synthesis in vascular smooth muscle cells (VSMCs) is very important in atherosclerosis, as it affects plaque stability. In this study, we aim to assess whether miR-124-3p is involved in the collagen synthesis process in VSMCs and the role it might play in atherosclerotic development. METHODS: We modulated the miR-124-3p expression in the aortic root plaques of high-fat-diet fed ApoE-/- mice by lentivirus injection. To determine plaque size and the content of plaque-stability-related cells or molecules, stainings, including hematoxylin and eosin, Oil red O, Sirius Red and immunohistochemical staining, were performed. Fluorescence in situ hybridization (FISH) was used to locate miR-124-3p in atherosclerotic plaques. Western blotting and RT-qPCR were carried out to determine the level of P4HA1 as well as type I and type III collagen protein and mRNA expression. RESULTS: Results showed that collagen and VSMC content of plaques was inversely correlated with miR-124-3p levels. By FISH, we identified that miR-124-3p was primarily expressed by VSMCs. We also found that protein levels of type I and type III collagen in aortas and atherosclerotic plaques were decreased by miR-124-3p. We modulated miR-124-3p level in vitro and found it could inhibit collagen expression in HASMCs. This might be caused by the downregulation of P4HA1. P4HA1 was predicted as miR-124-3p's direct target, which was verified with a dual luciferase reporter assay and RIP test. CONCLUSIONS: The results presented here provide evidence that miR-124-3p inhibits VSMC collagen synthesis by directly targeting P4HA1, which might decrease atherosclerotic plaque stability.


Assuntos
Aterosclerose/enzimologia , Colágeno/biossíntese , MicroRNAs/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Placa Aterosclerótica , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Animais , Aterosclerose/genética , Aterosclerose/patologia , Linhagem Celular , Modelos Animais de Doenças , Regulação Enzimológica da Expressão Gênica , Predisposição Genética para Doença , Humanos , Lipoproteínas LDL/metabolismo , Masculino , Camundongos Knockout para ApoE , MicroRNAs/genética , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Fenótipo , Pró-Colágeno-Prolina Dioxigenase/genética , Ruptura Espontânea , Transdução de Sinais
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