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1.
Life Sci ; 259: 118397, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32896557

RESUMO

There is increasing evidence that Bazedoxifene, as an FDA-approved selective estrogen inhibitor, approved by FDA, not only inhibits estrogen receptors, but also has other pharmacological effects. The purpose of this study was to investigate the effects of Bazedoxifene on the functional changes of vascular smooth muscle cells (VSMCs) after PDGF-BB stimulation. VSMCs were divided into control group, PDGF-BB treatment group, and PDGF-BB treatment group with different concentrations of Bazedoxifene. CCK-8 and EdU staining were used to determine the VSMCs viability and proliferation. Western blot was used to detect the expressions of vimentin, SMA, ERK, p-ERK, STAT3, p-STAT3, AKT, p-AKT, and LC3 I/II. Wound healing method was used to detect the migration of VSMCs. PDGF-BB treatment significantly enhanced the viability and proliferation of VSMCs as indicated by CCK-8 and EdU assays (P < 0.01), while Bazedoxifene pretreatment could reduce the increased viability and proliferation of VSMCs caused by PDGF-BB (P < 0.05). Wound healing test also showed Bazedoxifene significantly attenuated the migration in the PDGF-BB stimulated VSMCs (P < 0.01). PDGF-BB also induced the phenotypic switch and decreased the autophagy level in VSMCs, manifested as a reduction in vimentin, SMA, and LC3 II (P < 0.01). These effects of PDGF-BB were partially reversed by Bazedoxifene (P < 0.05). Bazedoxifene may inhibit the proliferation and migration of VSMCs through up-regulate the autophagy level after PDGF-BB stimulation.


Assuntos
Autofagia/efeitos dos fármacos , Becaplermina/farmacologia , Indóis/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Becaplermina/antagonistas & inibidores , Western Blotting , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Humanos , Músculo Liso Vascular/citologia , Fenótipo
2.
Life Sci ; 260: 118280, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32800835

RESUMO

AIMS: Vascular calcification is a common complication in patients with chronic kidney disease and associated with increased morbidity and mortality. The role of TRPM7 in vascular smooth muscle cell (VSMC) transformation during vascular calcification is not clear. We aim to investigate the effects of phosphate and indoxyl sulphate on the expression of TRPM7 and calcification-related molecules in VSMC. MAIN METHODS: Human aortic smooth muscle cells (HASMC) were treated with phosphate (3.3 mM) or indoxyl sulphate (500 µM and 1000 µM). 2-APB, a channel blocker of TRPM7 was added simultaneously in blocking experiment. Cells were then examined grossly and alizarin red solution was employed for calcification assessment. Lastly, cells were harvested for gene expression and protein abundance analysis. KEY FINDINGS: Phosphate treatment induced significant increase in BMP2, RUNX2, BMP7, vitamin D receptor (VDR), calcium sensing receptor (CaSR) and TRPM7, but 1-alpha hydroxylase, klotho, DKK1 and sclerostin were not changed. The addition of 2-APB prevented increase of BMP2, RUNX2, BMP7, VDR, CaSR and TRPM7. Indoxyl sulphate treatment was associated with decrease in TRPM7 and DKK1, but increase in RUNX2, BMP2 and VDR were noted. There were no significant alterations in BMP7, CaSR, klotho,1-alpha hydroxylase and sclerostin. Co-treatment with 2-APB reversed the increase in VDR. SIGNIFICANCE: Both phosphate and indoxyl sulphate induced calcification in VSMC but it was more prominent in phosphate. TRPM7 was upregulated by phosphate but downregulated in indoxyl sulphate treatment. Vascular calcification was reduced by blocking TRPM7 with 2-APB and there was partial anti-calcification effect in indoxyl sulphate.


Assuntos
Indicã/farmacologia , Músculo Liso Vascular/fisiologia , Miócitos de Músculo Liso/fisiologia , Fosfatos/farmacologia , Proteínas Serina-Treonina Quinases/fisiologia , Canais de Cátion TRPM/fisiologia , Calcificação Vascular/fisiopatologia , Proteína Morfogenética Óssea 2/análise , Proteína Morfogenética Óssea 7/análise , Células Cultivadas , Subunidade alfa 1 de Fator de Ligação ao Core/análise , Humanos , Músculo Liso Vascular/química , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/química , Miócitos de Músculo Liso/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/análise , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Receptores de Calcitriol/análise , Insuficiência Renal Crônica/complicações , Canais de Cátion TRPM/análise , Canais de Cátion TRPM/antagonistas & inibidores , Calcificação Vascular/induzido quimicamente , Calcificação Vascular/etiologia
3.
Life Sci ; 259: 118253, 2020 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-32795536

RESUMO

AIMS: We recently demonstrated that mechanical stretch increases the proliferation and apoptosis of vascular smooth muscle cells (VSMCs) by activating the protein disulfide isomerase (PDI) redox system, thus accelerating atherosclerotic lesion formation in the transplanted vein. At present, there are no efficient intervention measures to prevent this phenomenon. Berberine inhibits pathological vascular remodeling caused by hypertension, but the underlying mechanism is controversial. Herein, we investigate the role of berberine and the underlying mechanism of its effects on mechanical stretch-induced VSMC proliferation and apoptosis. MAIN METHODS: Mouse VSMCs cultivated on flexible membranes were pretreated for 1 h with one of the following substances: berberine, PDI inhibitor bacitracin, MAPK inhibitors, or ERS inhibitor 4-PBA. VSMCs were then subjected to mechanical stretch. Immunofluorescence and western blot were used to detect proliferation and apoptosis, as well as to analyze signaling pathways in VSMCs. KEY FINDINGS: Our results showed that berberine inhibits the PDI-endoplasmic reticulum stress system, thereby attenuating the simultaneous increase of VSMC proliferation and apoptosis in response to mechanical stretch. Interestingly, MAPK inhibitors PD98059, SP600125, and SB202190 significantly reduced the activation of ERS signaling cascades, and their combination with berberine had additive effects. The ERS inhibitor 4-PBA reduced PDI activation and ERS signaling, but not MAPK phosphorylation. Moreover, caspase-3 and caspase-12 were downregulated by berberine. SIGNIFICANCE: These results illustrate a novel mechanism of action of berberine that has practical implications. Our data provide important insights for the prevention and treatment of vascular remodeling and diseases caused by mechanical stretching during hypertension.


Assuntos
Berberina/farmacologia , Músculo Liso Vascular/metabolismo , Isomerases de Dissulfetos de Proteínas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Aterosclerose/metabolismo , Berberina/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , China , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Masculino , Fenômenos Mecânicos , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Oxirredução/efeitos dos fármacos , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Estresse Mecânico , Remodelação Vascular
4.
Int J Nanomedicine ; 15: 5239-5252, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801689

RESUMO

Introduction: The main pathological mechanism of restenosis after percutaneous coronary intervention (PCI) is intimal hyperplasia, which is mainly caused by proliferation and migration of vascular smooth muscle cells (VSMCs). Our previous study found that honokiol (HNK), a small-molecule polyphenol, can inhibit neointimal hyperplasia after balloon injury, but its specific mechanism is still unclear. Moreover, poor water solubility as well as low bioavailability of honokiol has limited its practical use. Methods: We used mesoporous silica nanoparticles (MSNPs) as a standard substance to encapsulate HNK and then assemble into honokiol-mesoporous silica nanoparticles, and we investigated the effect of these nanoparticles on the process of restenosis after common carotid artery injury in rats. Results: We report a promising delivery system that loads HNK into MSNPs and finally assembles it into a nanocomposite particle. These HNK-MSNPs not merely inhibited proliferation and migration of VSMCs by reducing phosphorylation of Smad3, but also showed a higher suppression of intimal thickening than the free-honokiol-treated group in a rat model of balloon injury. Conclusion: To sum up, this drug delivery system supplies a potent nano-platform for improving the biological effects of HNK and provides a promising strategy for preventing vascular restenosis.


Assuntos
Compostos de Bifenilo/farmacologia , Reestenose Coronária/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Lignanas/farmacologia , Nanopartículas/química , Intervenção Coronária Percutânea/efeitos adversos , Animais , Compostos de Bifenilo/administração & dosagem , Compostos de Bifenilo/farmacocinética , Lesões das Artérias Carótidas/etiologia , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/patologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Reestenose Coronária/metabolismo , Modelos Animais de Doenças , Humanos , Lignanas/administração & dosagem , Lignanas/farmacocinética , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Nanopartículas/administração & dosagem , Poloxâmero/química , Ratos Sprague-Dawley , Dióxido de Silício/química
5.
Arterioscler Thromb Vasc Biol ; 40(9): 2054-2069, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640907

RESUMO

OBJECTIVE: Increased CTSS (cathepsin S) has been reported to play a critical role in atherosclerosis progression. Both CTSS synthesis and secretion are essential for exerting its functions. However, the underlying mechanisms contributing to CTSS synthesis and secretion in atherosclerosis remain unclear. Approach and Results: In this study, we showed that nicotine activated autophagy and upregulated CTSS expression in vascular smooth muscle cells and in atherosclerotic plaques. Western blotting and immunofluorescent staining showed that nicotine inhibited the mTORC1 (mammalian target of rapamycin complex 1) activity, promoted the nuclear translocation of TFEB (transcription factor EB), and upregulated the expression of CTSS. Chromatin immunoprecipitation-qualificative polymerase chain reaction, electrophoretic mobility shift assay, and luciferase reporter assay further demonstrated that TFEB directly bound to the CTSS promoter. mTORC1 inhibition by nicotine or rapamycin promoted lysosomal exocytosis and CTSS secretion. Live cell assays and IP-MS (immunoprecipitation-mass spectrometry) identified that the interactions involving Rab10 (Rab10, member RAS oncogene family) and mTORC1 control CTSS secretion. Nicotine promoted vascular smooth muscle cell migration by upregulating CTSS, and CTSS inhibition suppressed nicotine-induced atherosclerosis in vivo. CONCLUSIONS: We concluded that nicotine mediates CTSS synthesis and secretion through regulating the autophagy-lysosomal machinery, which offers a potential therapeutic target for atherosclerosis treatment.


Assuntos
Aterosclerose/tratamento farmacológico , Autofagia/efeitos dos fármacos , Catepsinas/biossíntese , Lisossomos/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Nicotina/farmacologia , Animais , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Catepsinas/genética , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Exocitose , Lisossomos/enzimologia , Lisossomos/ultraestrutura , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos Knockout para ApoE , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/ultraestrutura , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/ultraestrutura , Via Secretória , Transdução de Sinais , Proteínas rab de Ligação ao GTP/genética , Proteínas rab de Ligação ao GTP/metabolismo
6.
Vascul Pharmacol ; 131: 106763, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32593718

RESUMO

Atherosclerosis (AS) is one of the most common cardiovascular events in patients with chronic renal insufficiency (CRI). During the development of CRI, uremic toxins, including indoxyl sulfate (IS), are pivotal risk factors for AS. However, the underlying mechanism between AS and IS has not been fully elucidated. The present study was designed to test our hypothesis that IS promotes the AS by regulating viability, proliferation, migration and apoptosis of endothelial cells and vascular smooth muscle cells. In this present study, our date showed that IS inhibited the cell viability of human umbilical vein endothelial cells (HUVECs) and human aortic vascular smooth muscle cells (HA-VSMCs) in a dose-dependent manner (P < .05). Moreover, IS inhibited the proliferation, migration and induced apoptosis of HUVECs and HA-VSMCs significantly (P < .05). However, inhibition of the miR-34a abolished these effects of IS in vitro, indicating that miR-34a is involved in the development of AS induced by IS. In addition, the luciferase reporter gene assay showed that up-regulating of miR-34a inhibited the Notch1 transcriptional activity remarkably (P < .05). The expression of Notch1 decreased after IS treatment, while miR-34a inhibitor attenuated this effect. Moreover, the expression of miR-34a-related proteins Wnt-1, Jag1, E2F1 and SIRT1 decreased, while the expression of p53 increased in HUVECs and HA-VSMCs after IS treatment. Consistently, blockage of miR-34a abolished the remarkable effects on protein expressions induced by IS. Taken together, this study showed that IS can inhibit the proliferation, migration and promote apoptosis of HUVECs and HA-VSMCs through the Notch1 signal and miR-34a-related proteins by up-regulating miR-34a. These findings may provide new insights into the underlying mechanism of AS in CRI.


Assuntos
Apoptose/efeitos dos fármacos , Aterosclerose/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Indicã/toxicidade , MicroRNAs/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Aterosclerose/genética , Aterosclerose/patologia , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , MicroRNAs/genética , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Receptor Notch1/genética , Receptor Notch1/metabolismo , Transdução de Sinais , Regulação para Cima
7.
Life Sci ; 256: 117986, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32585245

RESUMO

AIMS: HSP70, a molecular chaperone, helps to maintain proteostasis. In muscle biology, however, evidence suggests HSP70 to have a more versatile range of functions, as genetic deletion of its inducible genes impairs Ca2+ handling, and consequently, cardiac and skeletal muscle contractility. Still, it is unknown whether HSP70 is involved in vascular reactivity, an intrinsic physiological mechanism of blood vessels. Therefore, we designed this study to test the hypothesis that proper vascular reactivity requires the assistance of HSP70. MAIN METHODS: We performed functional studies in a wire-myograph using thoracic aorta isolated from male Sprague Dawley rats. Experiments were conducted with and without an HSP70 inhibitor as well as in heat-stressed vessels. The expression levels of HSP70 were evaluated with Western blotting. NO and ROS levels were assessed with fluorescence microscopy. KEY FINDINGS: We report that blockade of HSP70 weakens contraction in response to phenylephrine (dose-response) in the aorta. Additionally, we demonstrated that inhibition of HSP70 affects the amplitude of the fast and of the slow components of the time-force curve. Corroborating these findings, we found that inhibition of HSP70, in vessels over-expressing this protein, partly rescues the contractile phenotype of aortic rings. Furthermore, we show that blockade of HSP70 facilitates relaxation in response to acetylcholine and clonidine without affecting the basal levels of NO and ROS. SIGNIFICANCE: Our work introduces an additional physiological role for HSP70, the assistance of vascular reactivity, which highlights this protein as a new player in vascular physiology, and therefore, uncovers a promising research avenue for vascular diseases.


Assuntos
Aorta Torácica/fisiologia , Endotélio Vascular/fisiologia , Proteínas de Choque Térmico HSP70/fisiologia , Músculo Liso Vascular/fisiologia , Acetilcolina/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/agonistas , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Fenilefrina/farmacologia , Nucleosídeos de Purina/farmacologia , Ratos , Ratos Sprague-Dawley , Vasoconstritores/farmacologia , Vasodilatadores/farmacologia
8.
Cardiovasc Ther ; 2020: 6758934, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32565910

RESUMO

Background: Atherosclerosis (AS) is a common severe disease around the world. The merging paper reported that long noncoding RNAs (lncRNAs) took part in diversified pathological processes of AS, although the mechanism remains unknown. This study is aimed at uncovering the profile of lncRNA taurine-upregulated gene 1 (TUG1), which has biological function, and potential mechanism in AS progression in vitro. Methods: Oxidized low-density lipoprotein (ox-LDL) was used for AS model construction in vitro. Levels of lncRNA TUG1, miR-141-3p, and receptor tyrosine kinase-like orphan receptor 2 (ROR2) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) in AS tissues or in ox-LDL-treated vascular smooth muscle cells (HA-VSMCs). The biofunctional effects were examined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and transwell assays. The expression of proliferation-related proteins (CyclinD1, Ki-67) and metastasis-associated proteins (ß-catenin, Vimentin) and ROR2 in cells was determined by western blot analysis. The potential binding sites were predicted by starBase software online and confirmed by dual-luciferase reporter analysis. Results: The expression of TUG1 and ROR2 was promoted in AS tissues and ox-LDL-treated HA-VSMCs. While the low expression of miR-141-3p negatively correlated with that of TUG1 or ROR2 in AS tissues. Silencing of TUG1 inhibited the proliferation, migration, invasion, and metastasis in ox-LDL-treated HA-VSMCs. Moreover, the putative binding sites between miR-141-3p and TUG1 or ROR2 were predicted by starBase software online. Also, miR-141-3p deletion reversed the positive effects of TUG1 knockdown on cells. Besides, downregulation of miR-141-3p disrupted the biofunctional results from ROR2 silencing. Conclusion: TUG1 enhanced the progression of AS in vitro by regulating the miR-141-3p/ROR2 axis.


Assuntos
Aterosclerose/metabolismo , Lipoproteínas LDL/toxicidade , MicroRNAs/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , RNA Longo não Codificante/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Aterosclerose/genética , Aterosclerose/patologia , Estudos de Casos e Controles , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica , Humanos , MicroRNAs/genética , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Placa Aterosclerótica , RNA Longo não Codificante/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Transdução de Sinais
9.
Cardiovasc Pathol ; 49: 107230, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32585603

RESUMO

PURPOSE: Restenosis is the main complication after percutaneous coronary intervention. The proliferation of new intima contributes to the process. In this study, we aimed to explore the effect of olmesartan on intimal thickening after balloon injury and possible mechanism. METHODS: Aortic endothelial denudation model was made by a 2F balloon catheter. Thirty-six rats were randomly allocated into three groups: Control (n = 12) Surgery (n = 12, received vascular balloon injury) and Olmesartan (n = 12, received 3 mg.kg-1.d-1olmesartan after injury). Fourteen and 28 days after injury, HE staining was used to assess the aortic endothelial injury. Radioimmunological method was used to examine the level of angiotensin II (Ang II). Western blotting and reverse transcription polymerse chain reaction (RT-PCR) were employed to detect the protein and mRNA level of Apelin/APJ. RESULTS: After vascular balloon injury, the proliferation of vascular smooth muscle cells and the intimal thickening were increased. The mRNA and protein level of Ang II, AT1, Apelin and APJ mRNA were promoted by vascular balloon injury. Olmesartan decreased the proliferation of vascular smooth muscle cells and the intimal thickening. Olmesartan decreased the expression of Ang II and AT1, but further increased the expression of Apelin and APJ. Balloon injury also induced the activation of Extracellular signal-regulated kinase (ERK) signaling and olmesartan decreased the effect. CONCLUSION: Olmesartan inhibits the intimal thickening through activating Apelin/APJ and inhibiting AngII-AT1 and ERK pathway.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Receptores de Apelina/metabolismo , Apelina/metabolismo , Imidazóis/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Neointima , Tetrazóis/farmacologia , Lesões do Sistema Vascular/tratamento farmacológico , Angioplastia com Balão , Angiotensina II/metabolismo , Animais , Aorta/efeitos dos fármacos , Aorta/lesões , Aorta/metabolismo , Aorta/patologia , Proliferação de Células/efeitos dos fármacos , Constrição Patológica , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Masculino , Músculo Liso Vascular/lesões , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Fosforilação , Ratos Wistar , Receptor Tipo 1 de Angiotensina/metabolismo , Transdução de Sinais , Lesões do Sistema Vascular/etiologia , Lesões do Sistema Vascular/metabolismo , Lesões do Sistema Vascular/patologia
10.
Vascul Pharmacol ; 130: 106681, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32387336

RESUMO

Vascular calcification (VC) is a common complication of chronic kidney disease (CKD). However, its mechanisms remain unclear. VC, similar to atherosclerosis, is an inflammatory disease. Vascular smooth muscle cells (VSMCs) play a key role in VC progression. The androgen receptor (AR) in monocytes/macrophages plays an important role in inflammatory diseases. Here, we define the role of macrophage (MФ) AR in inorganic phosphate-induced VSMC calcification. Our results show that the conditioning medium (CM) of silencing AR in macrophages inhibits inorganic phosphate-induced human aortic smooth muscle cell (HASMC) calcification, and alleviates the transdifferentiation of HASMCs into osteoblasts for the protein expression of osteoblasts marker Runt-related transcription factor-2 (Runx2) in HASMCs decreased while that of smooth muscle cell marker SM22α increased. The effect of AR on HASMC calcification might mainly be mediated by the inflammatory cytokine IL-6. Silencing AR in monocytes/macrophages can dramatically decrease IL-6 expression. We also investigated how macrophage AR regulates IL-6. ChIP and luciferase assays indicate that AR directly binds to the ARE sequence in the promoter of the IL-6 gene to accelerate transcription and expression. To our knowledge, this is the first investigation that has established the correlation between AR and VC and identified the contribution of AR in the calcification of VSMCs. In addition, this study describes a novel target for therapeutic intervention in VC.


Assuntos
Interleucina-6/metabolismo , Macrófagos/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Comunicação Parácrina , Fosfatos/toxicidade , Receptores Androgênicos/metabolismo , Calcificação Vascular/metabolismo , Actinas/metabolismo , Transdiferenciação Celular/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/metabolismo , Regulação para Baixo , Humanos , Interleucina-6/genética , Macrófagos/patologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Osteoblastos/efeitos dos fármacos , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteogênese/efeitos dos fármacos , Receptores Androgênicos/genética , Transdução de Sinais , Células THP-1 , Calcificação Vascular/genética , Calcificação Vascular/patologia
11.
Vascul Pharmacol ; 131: 106690, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32407896

RESUMO

Cutaneous cold-induced vasoconstriction is a normal physiological reaction mediated by alpha 2C-adrenergic receptors (α2C-ARs) expressed in vascular smooth muscle cells (VSMCs). When this reaction is exaggerated, Raynaud's phenomenon (RP) ensues. RP is more prevalent in females compared to age-matched men. We previously established that 17-ß estradiol (estrogen) upregulates α2C-ARs in human VSMCs via a cAMP/Epac/Rap pathway. We also showed that cAMP acts through JNK to increase α2C-AR expression. However, whether estrogen employs JNK to regulate α2C-AR is not investigated. Knowing that the α2C-AR promoter harbors an activator protein-1 (AP-1) binding site that can be potentially activated by JNK, we hypothesized that estrogen regulates α2C-AR expression through an Epac/JNK/AP-1 pathway. Our results show that estrogen (10-10 M) activated JNK in human VSMCs extracted from cutaneous arterioles. Pretreatment with ESI09 (10 µM; an Epac inhibitor), abolished estrogen-induced JNK activation. In addition, pre-treatment with SP600125 (3 µM; a JNK specific inhibitor) abolished estrogen-induced expression of α2C-AR. Importantly, estrogen-induced activation of α2C-AR promoter was attenuated with SP600125. Moreover, transient transfection of VSMCs with an Epac dominant negative mutant (Epac-DN) abolished estrogen-induced activation of α2C-AR promoter. However, co-transfection of constitutively active JNK mutant overrode the inhibitory effect of Epac-DN on α2C-AR promoter. Moreover, estrogen caused a concentration-dependent increase in the activity of AP-1-driven reporter construct. Mutation of AP-1 site in the α2C-AR promoter abolished its activation by estrogen. This in vitro estrogen-increased α2C-AR expression was mirrored by an increase in the ex vivo functional responsiveness of arterioles. Indeed, estrogen potentiated α2C-AR-mediated cold-induced vasoconstriction, which was abolished by SP600125. Collectively, these results indicate that estrogen upregulates α2C-AR expression via an EPAC-mediated JNK/AP-1- dependent mechanism. These results provide an insight into the mechanism by which exaggerated cold-induced vasoconstriction occurs in estrogen-replete females and identify Epac and JNK as potential targets for the treatment of RP.


Assuntos
Temperatura Baixa , AMP Cíclico/metabolismo , Estradiol/farmacologia , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Receptores Adrenérgicos alfa 2/metabolismo , Cauda/irrigação sanguínea , Fator de Transcrição AP-1/metabolismo , Vasoconstrição/efeitos dos fármacos , Animais , Arteríolas/efeitos dos fármacos , Arteríolas/enzimologia , Células Cultivadas , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Doença de Raynaud/tratamento farmacológico , Doença de Raynaud/enzimologia , Doença de Raynaud/fisiopatologia , Receptores Adrenérgicos alfa 2/genética , Transdução de Sinais , Fator de Transcrição AP-1/genética , Regulação para Cima
12.
Cell Physiol Biochem ; 54(3): 371-383, 2020 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-32298554

RESUMO

BACKGROUND/AIMS: This study aimed to establish a precise and well-defined working model, assessing pharmaceutical effects on vascular smooth muscle cell monolayer in-vitro. It describes various analysis techniques to determine the most suitable to measure the biomechanical impact of vasoactive agents by using CellDrum technology. METHODS: The so-called CellDrum technology was applied to analyse the biomechanical properties of confluent human aorta muscle cells (haSMC) in monolayer. The cell generated tensions deviations in the range of a few N/m² are evaluated by the CellDrum technology. This study focuses on the dilative and contractive effects of L-type Ca2+ channel agonists and antagonists, respectively. We analyzed the effects of Bay K8644, nifedipine and verapamil. Three different measurement modes were developed and applied to determine the most appropriate analysis technique for the study purpose. These three operation modes are called, particular time mode" (PTM), "long term mode" (LTM) and "real-time mode" (RTM). RESULTS: It was possible to quantify the biomechanical response of haSMCs to the addition of vasoactive agents using CellDrum technology. Due to the supplementation of 100nM Bay K8644, the tension increased approximately 10.6% from initial tension maximum, whereas, the treatment with nifedipine and verapamil caused a significant decrease in cellular tension: 10nM nifedipine decreased the biomechanical stress around 6,5% and 50nM verapamil by 2,8%, compared to the initial tension maximum. Additionally, all tested measurement modes provide similar results while focusing on different analysis parameters. CONCLUSION: The CellDrum technology allows highly sensitive biomechanical stress measurements of cultured haSMC monolayers. The mechanical stress responses evoked by the application of vasoactive calcium channel modulators were quantified functionally (N/m²). All tested operation modes resulted in equal findings, whereas each mode features operation-related data analysis.


Assuntos
Biofísica/métodos , Músculo Liso Vascular/efeitos dos fármacos , Vasoconstritores/farmacologia , Éster Metílico do Ácido 3-Piridinacarboxílico, 1,4-Di-Hidro-2,6-Dimetil-5-Nitro-4-(2-(Trifluormetil)fenil)/farmacologia , Aorta/efeitos dos fármacos , Fenômenos Biomecânicos , Biofísica/instrumentação , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo L/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Humanos , Nifedipino/farmacologia , Estresse Mecânico , Vasoconstrição , Verapamil/farmacologia
13.
Rev Med Suisse ; 16(688): 652-656, 2020 Apr 01.
Artigo em Francês | MEDLINE | ID: mdl-32239840

RESUMO

Vasopressin (AVP) is a posterior pituitary hormone initially known for its antidiuretic actions. In this article, we recall the biochemical and pharmacological characteristics of the AVP and its analogues. Currently, its main indication in critical care medicine is vasoplegic shock in view of its vasopressive properties. This strong vasopressive activity is related to the activation of V1 receptors located in the vascular smooth muscle. The scientific evidence of the AVP therapy, and its potential benefits versus norepinephrine in vasoplegic shock, is reviewed in this article. Similarly, we present the other indications of vasopressin in the critical patient, based on recent studies and international guidelines.


Assuntos
Arginina Vasopressina/metabolismo , Arginina Vasopressina/uso terapêutico , Estado Terminal , Vasoplegia/tratamento farmacológico , Humanos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Norepinefrina/uso terapêutico , Receptores de Vasopressinas/metabolismo
14.
Cardiovasc Ther ; 2020: 1926249, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32328171

RESUMO

Isoliquiritigenin (ISL) is a flavonoid isolated mainly from the licorice plant, a traditional Chinese herb. ISL has shown anticancer, anti-inflammatory, antioxidant, and antidiabetic activities. However, the pharmaceutical effects of ISL on atherosclerosis are seldom explored. In this study, we used apolipoprotein E (ApoE) knockout mouse model and angiotensin II- (Ang II-) stimulated vascular smooth muscle cells (VSMCs) to elucidate the pharmacological mechanism of ISL to inhibit atherosclerosis. We found that in ApoE-/- mice ISL could attenuate atherosclerotic lesion, reduce serum lipid levels, and inhibit TRPC5 expression. In vitro, ISL inhibited Ang II-stimulated proliferation of VSMCs and suppressed Ang II-induced TRPC5 and PCNA expressions in a dose-dependent fashion. In conclusion, our findings provide novel insight into the pharmacological effects of ISL on atherosclerosis and suggest that ISL is beneficial for cardiovascular protection.


Assuntos
Aorta/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Chalconas/farmacologia , Placa Aterosclerótica , Canais de Cátion TRPC/antagonistas & inibidores , Animais , Aorta/metabolismo , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Lipídeos/sangue , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Transdução de Sinais , Canais de Cátion TRPC/metabolismo
15.
Artigo em Inglês | MEDLINE | ID: mdl-32267714

RESUMO

Essential hypertension is associated with impairments in vascular function and sympathetic nerve hyperactivity; however, the extent to which the lower limbs are affected remains unclear. We examined the leg vascular responsiveness to infusion of acetylcholine (ACh), sodium nitroprusside (SNP), and phenylephrine (PEP) in 10 hypertensive men [HYP: age 59.5 ± 9.7 (means ± SD) yr; clinical and nighttime blood pressure: 142 ± 10/86 ± 10 and 141 ± 11/83 ± 6 mmHg, respectively; and body mass index (BMI): 29.2 ± 4.0 kg/m2] and 8 age-matched normotensive counterparts (NORM: age 57.9 ± 10.8 yr; clinical and nighttime blood pressure: 128 ± 9/78 ± 7 and 116 ± 3/69 ± 3 mmHg, respectively; and BMI: 26.3 ± 3.1 kg/m2). The vascular responsiveness was evaluated before and after 6 wk of 10-20-30 training, consisting of 3 × 5 × 10-s sprint followed by 30 and 20 s of low- to moderate-intensity cycling, respectively, interspersed by 3 min of rest. Before training, the vascular responsiveness to infusion of SNP was lower (P < 0.05) in HYP compared with NORM, with no difference in the responsiveness to infusion of ACh and PEP. The vascular responsiveness to infusion of SNP and ACh improved (P < 0.05) with training in HYP, with no change in NORM. With training, intra-arterial systolic blood pressure decreased (P < 0.05) by 9 mmHg in both HYP and NORM whereas diastolic blood pressure decreased (5 mmHg; P < 0.05) in HYP only. We provide here the first line of evidence in humans that smooth muscle cell vasodilator responsiveness is blunted in the lower limbs of hypertensive men. This impairment can be reversed by 10-20-30 training, which is an effective intervention to improve the responsiveness of smooth muscle cells in men with essential hypertension.


Assuntos
Pressão Sanguínea , Hipertensão Essencial/terapia , Treinamento Intervalado de Alta Intensidade , Extremidade Inferior/irrigação sanguínea , Músculo Liso Vascular/fisiopatologia , Vasodilatação , Idoso , Pressão Sanguínea/efeitos dos fármacos , Hipertensão Essencial/diagnóstico , Hipertensão Essencial/fisiopatologia , Humanos , Infusões Intra-Arteriais , Masculino , Pessoa de Meia-Idade , Músculo Liso Vascular/efeitos dos fármacos , Fluxo Sanguíneo Regional , Fatores de Tempo , Resultado do Tratamento , Vasodilatação/efeitos dos fármacos , Vasodilatadores/administração & dosagem
16.
Am J Respir Cell Mol Biol ; 63(2): 160-171, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32255665

RESUMO

Mutations in the gene encoding BMPR2 (bone morphogenetic protein type 2 receptor) are the major cause of heritable pulmonary arterial hypertension (PAH). Point mutations in the BMPR2 ligand-binding domain involving cysteine residues (such as C118W) are causative of PAH and predicted to cause protein misfolding. Using heterologous overexpression systems, we showed previously that these mutations lead to retention of BMPR2 in the endoplasmic reticulum but are partially rescued by chemical chaperones. Here, we sought to determine whether the chemical chaperone 4-phenylbutyrate (4PBA) restores BMPR2 signaling in primary cells and in a knockin mouse harboring a C118W mutation. First, we confirmed dysfunctional BMP signaling in dermal fibroblasts isolated from a family with PAH segregating the BMPR2 C118W mutation. After BMP4 treatment, the induction of downstream signaling targets (Smad1/5, ID1 [inhibitor of DNA binding 1], and ID2) was significantly reduced in C118W mutant cells. Treatment with 4PBA significantly rescued Smad1/5, ID1, and ID2 expression. Pulmonary artery smooth muscle cells isolated from the lungs of heterozygous mice harboring the Bmpr2 C118W mutation exhibited significantly increased proliferation. In the presence of 4PBA, hyperproliferation was dramatically reduced. Furthermore, in vivo, 4PBA treatment of Bmpr2 C118W mice partially rescued Bmpr2 expression, restored downstream signaling, and improved vascular remodeling. These findings demonstrate in primary cells and in a knockin mouse that the repurposed small-molecule chemical chaperone 4PBA might be a promising precision medicine approach to treat PAH in patients with specific subtypes of BMPR2 mutation involving cysteine substitutions in the ligand-binding domain.


Assuntos
Receptores de Proteínas Morfogenéticas Ósseas Tipo II/genética , Cisteína/genética , Mutação/genética , Compostos Organofosforados/farmacologia , Hipertensão Arterial Pulmonar/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Animais , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Células Cultivadas , Humanos , Camundongos , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Hipertensão Arterial Pulmonar/genética , Artéria Pulmonar/efeitos dos fármacos , Transdução de Sinais/genética , Remodelação Vascular/efeitos dos fármacos , Remodelação Vascular/genética
17.
Toxicol Appl Pharmacol ; 398: 115012, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32320793

RESUMO

INTRODUCTION: Crotonaldehyde (CR) is an electrophilic α,ß-unsaturated aldehyde present in foods and beverages and is a minor metabolite of 1,3-butadiene. CR is a product of incomplete combustion, and is at high levels in smoke of cigarettes and structural fires. Exposure to CR has been linked to cardiopulmonary toxicity and cardiovascular disease. OBJECTIVE: The purpose of this study was to examine the direct effects of CR in murine blood vessels (aorta and superior mesenteric artery, SMA) using an in vitro system. METHODS AND RESULTS: CR induced concentration-dependent (1-300 µM) relaxations (75-80%) in phenylephrine (PE) precontracted aorta and SMA. Because the SMA was 20× more sensitive to CR than aorta (SMA EC50 3.8 ± 0.5 µM; aorta EC50 76.0 ± 2.0 µM), mechanisms of CR relaxation were studied in SMA. The CR-induced relaxation at low concentrations (1-30 µM) was inhibited by: 1) mechanically-impaired endothelium; 2) Nω-Nitro-L-arginine methyl ester hydrochloride (L-NAME); 3) guanylyl cyclase (GC) inhibitor (ODQ); 4) transient receptor potential ankyrin-1 (TRPA1) antagonist (A967079); and, 5) by non-vasoactive level of nicotine (1 µM). Similarly, a TRPA1 agonist, allyl isothiocyanate (AITC; mustard oil), stimulated SMA relaxation dependent on TRPA1, endothelium, NO, and GC. Consistent with these mechanisms, TRPA1 was present in the SMA endothelium. CR, at higher concentrations (100-300 µM), induced tension oscillations (spasms) and irreversibly impaired contractility (a vasotoxic effect enhanced by impaired endothelium). CONCLUSIONS: CR relaxation depends on a functional endothelium and TRPA1, whereas vasotoxicity is enhanced by endothelium dysfunction. Thus, CR is both vasoactive and vasotoxic along a concentration continuum.


Assuntos
Aldeídos/farmacologia , Aorta Torácica/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Canal de Cátion TRPA1/metabolismo , Vasodilatação/efeitos dos fármacos , Animais , Aorta Torácica/metabolismo , Endotélio Vascular/metabolismo , Feminino , Masculino , Camundongos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Fenilefrina/metabolismo
18.
PLoS One ; 15(3): e0227316, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32126062

RESUMO

Alpha adrenergic stimulation is known to produce vasoconstriction. We have earlier shown that, in spiral strips of small arteries Phenylephrine (PE) caused vasorelaxation under high nitric oxide (NO) environment. However, on further experimentation it was realized that the PE-induced vasorelaxant response occurred only with longitudinal strips of small arteries even under normal NO environment while circular strips showed contraction with PE even under high NO environment. Such PE-induced vasorelaxation of longitudinal strips was blocked by Phentolamine, an alpha-adrenergic receptor blocker. On delineation of specific receptor subtype, PE-induced relaxation was found to be mediated through alpha 1D receptor. However, this phenomenon is specific to small artery, as longitudinal smooth muscle of aorta showed only contractile response to adrenergic stimulation. There is no prior report of longitudinal smooth muscle in small artery up to our knowledge. The results of this study and histological examination of vessel sections suggest the presence of longitudinal smooth muscle in small artery and their relaxant response to alpha adrenergic stimulation is a novel phenomenon.


Assuntos
Agonistas de Receptores Adrenérgicos alfa 1/farmacologia , Artérias/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Fenilefrina/farmacologia , Vasodilatação/efeitos dos fármacos , Animais , Artérias/fisiologia , Cabras , Extremidade Inferior/irrigação sanguínea , Músculo Liso Vascular/fisiologia
19.
Braz J Med Biol Res ; 53(3): e8853, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32130289

RESUMO

Anaphylactic shock can be defined as an acute syndrome, and it is the most severe clinical manifestation of allergic diseases. Anaphylactoid reactions are similar to anaphylactic events but differ in the pathophysiological mechanism. Nitric oxide (NO) inhibitors during anaphylaxis suggest that NO might decrease the signs and symptoms of anaphylaxis but exacerbate associated vasodilation. Therefore, blocking the effects of NO on vascular smooth muscle by inhibiting the guanylate cyclase (GC) would be a reasonable strategy. This study aimed to investigate the effects of NO/cGMP pathway inhibitors methylene blue (MB), Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME), and indigo carmine (IC) in shock induced by compound 48/80 (C48/80) in rats. The effect was assessed by invasive blood pressure measurement. Shock was initiated by C48/80 intravenous bolus injection 5 min before (prophylactic) or after (treatment) the administration of the inhibitors MB (3 mg/kg), L-NAME (1 mg/kg), and IC (3 mg/kg). Of the groups that received drugs as prophylaxis for shock, only the IC group did not present the final systolic blood pressure (SBP) better than the C48/80 group. Regarding shock treatment with the drugs tested, all groups had the final SBP similar to the C48/80group. Altogether, our results suggested that inhibition of GC and NO synthase in NO production pathway was not sufficient to revert hypotension or significantly improve survival.


Assuntos
Anafilaxia/tratamento farmacológico , GMP Cíclico/antagonistas & inibidores , Inibidores Enzimáticos/administração & dosagem , Músculo Liso Vascular/efeitos dos fármacos , Óxido Nítrico/antagonistas & inibidores , Animais , Modelos Animais de Doenças , Índigo Carmim/administração & dosagem , Masculino , Azul de Metileno/administração & dosagem , NG-Nitroarginina Metil Éster/administração & dosagem , Ratos , Ratos Wistar
20.
Arterioscler Thromb Vasc Biol ; 40(5): 1256-1274, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32160773

RESUMO

OBJECTIVE: In view of our previous observations on differential expression of LMCD1 (LIM and cysteine-rich domains 1) in human versus rodents, we asked the question whether LMCD1 plays a species-specific role in the development of vascular lesions. Approach and Results: A combination of genetic, molecular, cellular, and disease models were used to test species-specific role of LMCD1 in the pathogenesis of vascular lesions. Here, we report species-specific regulation of LMCD1 expression in mediating vascular smooth muscle cell proliferation and migration during vascular wall remodeling in humans versus mice. Thrombin induced LMCD1 expression in human aortic smooth muscle cells but not mouse aortic smooth muscle cells via activation of Par1 (protease-activated receptor 1)-Gαq/11 (Gα protein q/11)-PLCß3 (phospholipase Cß3)-NFATc1 (nuclear factor of activated T cells 1) signaling. Furthermore, although LMCD1 mediates thrombin-induced proliferation and migration of both human aortic smooth muscle cells and mouse aortic smooth muscle cells via influencing E2F1 (E2F transcription factor 1)-mediated CDC6 (cell division cycle 6) expression and NFATc1-mediated IL (interleukin)-33 expression, respectively, in humans, it acts as an activator, and in mice, it acts as a repressor of these transcriptional factors. Interestingly, LMCD1 repressor activity was nullified by N-myristoyltransferase 2-mediated myristoylation in mouse. Besides, we found increased expression of LMCD1 in human stenotic arteries as compared to nonstenotic arteries. On the other hand, LMCD1 expression was decreased in neointimal lesions of mouse injured arteries as compared to noninjured arteries. CONCLUSIONS: Together, these observations reveal that LMCD1 acts as an activator and repressor of E2F1 and NFATc1 in humans and mice, respectively, in the induction of CDC6 and IL-33 expression during development of vascular lesions. Based on these findings, LMCD could be a potential target for drug development against restenosis and atherosclerosis in humans.


Assuntos
Proteínas Correpressoras/metabolismo , Fator de Transcrição E2F1/metabolismo , Interleucina-33/metabolismo , Proteínas com Domínio LIM/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fatores de Transcrição NFATC/metabolismo , Remodelação Vascular , Lesões do Sistema Vascular/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Movimento Celular , Proliferação de Células , Células Cultivadas , Proteínas Correpressoras/genética , Modelos Animais de Doenças , Fator de Transcrição E2F1/genética , Feminino , Regulação da Expressão Gênica , Humanos , Interleucina-33/genética , Proteínas com Domínio LIM/genética , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Ácido Mirístico/metabolismo , Fatores de Transcrição NFATC/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Processamento de Proteína Pós-Traducional , Transdução de Sinais , Especificidade da Espécie , Trombina/farmacologia , Remodelação Vascular/efeitos dos fármacos , Lesões do Sistema Vascular/genética , Lesões do Sistema Vascular/patologia
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