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1.
Life Sci ; 246: 117419, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32045592

RESUMO

AIMS: Although resistin-like molecule ß (RELM-ß) is involved in the pathological processes of various lung diseases, such as pulmonary inflammation, asthma and fibrosis, its potential roles in hypoxic pulmonary arterial hypertension (PAH) remain largely unknown. The study aims to investigate whether RELM-ß contributes to hypoxia-induced excessive proliferation of human pulmonary artery smooth muscle cells (PASMCs) and to explore the potential mechanisms of this process. MAIN METHODS: Human PASMCs were exposed to normoxia or hypoxia (1% O2) for 24 h. siRNA targeting RELM-ß was transfected into cells. Protein levels of KCNK3, RELM-ß, pSTAT3 and STAT3 were determined by immunoblotting. The translocation of NFATc2 and expression of KCNK3 were visualized by immunofluorescence. 5-ethynyl-2'-deoxyuridine assays and cell counting kit-8 assays were performed to assess the proliferation of PASMCs. KEY FINDINGS: (1) Chronic hypoxia significantly decreased KCNK3 protein levels while upregulating RELM-ß protein levels in human PASMCs, which was accompanied by excessive proliferation of cells. (2) RELM-ß could promote human PASMCs proliferation and activate the STAT3/NFAT axis by downregulating KCNK3 protein under normoxia. (3) Inhibition of RELM-ß expression effectively prevented KCNK3-mediated cell proliferation under hypoxia. (4) Phospholipase C (PLC) inhibitor U-73122 could not only prevent the hypoxia/RELM-ß-induced decrease in KCNK3 protein, but also inhibit the enhanced cell viability caused by hypoxia/RELM-ß. (5) Both hypoxia and RELM-ß could downregulate membrane KCNK3 protein levels by enhancing endocytosis. SIGNIFICANCE: RELM-ß activation is responsible for hypoxia-induced excessive proliferation of human PASMCs. Interfering with RELM-ß may alleviate the progression of hypoxic PAH by upregulating PLC-dependent KCNK3 expression.


Assuntos
Hipóxia/complicações , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Canais de Potássio de Domínios Poros em Tandem/metabolismo , Artéria Pulmonar/efeitos dos fármacos , Fosfolipases Tipo C/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Imunofluorescência , Humanos , Hipóxia/tratamento farmacológico , Músculo Liso Vascular/citologia , Músculo Liso Vascular/crescimento & desenvolvimento , Artéria Pulmonar/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais
2.
Cell Prolif ; 53(2): e12742, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31943454

RESUMO

OBJECTIVES: Hypoxia is an important risk factor for pulmonary arterial remodelling in pulmonary arterial hypertension (PAH), and the Janus kinase 2 (JAK2) is believed to be involved in this process. In the present report, we aimed to investigate the role of JAK2 in vascular smooth muscle cells during the course of PAH. METHODS: Smooth muscle cell (SMC)-specific Jak2 deficient mice and their littermate controls were subjected to normobaric normoxic or hypoxic (10% O2 ) challenges for 28 days to monitor the development of PAH, respectively. To further elucidate the potential mechanisms whereby JAK2 influences pulmonary vascular remodelling, a selective JAK2 inhibitor was applied to pre-treat human pulmonary arterial smooth muscle cells (HPASMCs) for 1 hour followed by 24-hour hypoxic exposure. RESULTS: Mice with hypoxia-induced PAH were characterized by the altered JAK2/STAT3 activity in pulmonary artery smooth muscle cells. Therefore, induction of Jak2 deficiency in SMCs protected mice from hypoxia-induced increase of right ventricular systolic pressure (RVSP), right ventricular hypertrophy and pulmonary vascular remodelling. Particularly, loss of Jak2 significantly attenuated chronic hypoxia-induced PASMC proliferation in the lungs. Similarly, blockade of JAK2 by its inhibitor, TG-101348, suppressed hypoxia-induced human PASMC proliferation. Upon hypoxia-induced activation, JAK2 phosphorylated signal transducer and activator of transcription 3 (STAT3), which then bound to the CCNA2 promoter to transcribe cyclin A2 expression, thereby promoting PASMC proliferation. CONCLUSIONS: Our studies support that JAK2 could be a culprit contributing to the pulmonary vascular remodelling, and therefore, it could be a viable target for prevention and treatment of PAH in clinical settings.


Assuntos
Proliferação de Células/fisiologia , Hipóxia/metabolismo , Janus Quinase 2/antagonistas & inibidores , Miócitos de Músculo Liso/metabolismo , Artéria Pulmonar/metabolismo , Animais , Proliferação de Células/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/patologia , Hipóxia/patologia , Janus Quinase 2/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Knockout , 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/patologia , Inibidores de Proteínas Quinases/farmacologia , /metabolismo , Artéria Pulmonar/patologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Remodelação Vascular/efeitos dos fármacos , Remodelação Vascular/fisiologia
3.
Life Sci ; 241: 117098, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31794773

RESUMO

INTRODUCTION: Sepsis survivors are at higher risk for cardiovascular events. Lipopolysaccharide (LPS) activates Toll-like receptor 4 (TLR4) in sepsis. Activation of TLR4 modulates vascular smooth muscle cells (VSMCs) phenotype and contributes to cardiovascular changes after sepsis. AIM: Investigate changes in VSMCs phenotype caused by LPS-induced TLR4 activation. METHODS: Rat VSMCs were incubated with LPS. Two incubation conditions were used in cell contraction and migration assays: acute stimulation - LPS stimulus was initiated at the beginning of the assay and maintained throughout; and preconditioning - LPS stimulation was applied prior to the assay then discontinued. Nitric oxide (NO) production, mRNA expression of cytokines and phenotype markers, and interleukin (IL)-6 production were evaluated. KEY FINDINGS: LPS increased gene expression of IL-1ß, IL-6, TNFα and MCP-1 (p < .001), of secretory phenotype markers collagen and vimentin (p < .0479) and of the contractile marker smooth muscle 22α (SM22α) (p = .0067). LPS exposure increased IL-6 secretion after 24 and 48 h (p < .0001), and NO at 8 and 24 h (p < .0249) via inducible nitric oxide synthase (iNOS), as demonstrated by a decrease in NO after incubation with aminoguanidine. Acute stimulation with LPS reduced migration and contraction in a NO-dependent manner, while preconditioning with LPS increased both in an IL-6-dependent manner. SIGNIFICANCE: LPS affects VSMCs by modulating their secretory, contractile and migratory phenotypes. LPS acute stimulation of VSMCs promoted a NO-dependent reduction in migration and contraction, while preconditioning with LPS promoted IL-6-dependent increases in migration and contraction, evidencing that VSMCs can present phenotype modifications that persist after sepsis, thereby contributing to postsepsis cardiovascular events.


Assuntos
Lipopolissacarídeos/toxicidade , Contração Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Sepse/fisiopatologia , Animais , Aorta Torácica/citologia , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Contração Muscular/fisiologia , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiologia , Óxido Nítrico , Fenótipo , Ratos Wistar
4.
Life Sci ; 242: 117159, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31837334

RESUMO

AIMS: It has been shown that up-regulation of E3 ubiquitin ligase seven-in-absentia-homolog 2 (Siah2) and activation of Hippo signaling pathway effector yes-associated protein (YAP) are involved in the development of pulmonary arterial hypertension (PAH). However, it is still unclear whether Siah2 activates YAP in monocrotaline (MCT)-induced PAH rat models. MAIN METHODS: Intraperitoneal injection of MCT was used to induce PAH rat models. The right ventricular systolic pressure (RVSP), right ventricle hypertrophy index (RVHI), percentage of medial wall thickness (%MT), α-SMA, Ki-67 and TUNEL staining were performed to evaluate the development of PAH. Protein levels of Siah2, Lats1/2, YAP phosphorylation and total YAP, and the subcellular localization of YAP were examined using immunoblotting. Proteasome activity was measured by an assay kit. KEY FINDINGS: The protein level of Siah2 was significantly increased in MCT-induced PAH rats, this was accompanied with the proteasome-dependent degradation of Lats1/2 and subsequent up-regulation and dephosphorylation of YAP and its nuclear localization. Administration of PAH rats with Siah2 inhibitor Vitamin K3 or proteasome inhibitor MG-132 dramatically suppressed MCT-induced down-regulation of Lats1/2 and activation of YAP, finally reduced RVSP, RVHI, %MT, pulmonary arterial muscularization, pulmonary arterial smooth muscle cells (PASMCs) proliferation and enhanced PASMCs apoptosis in PAH rats. SIGNIFICANCE: Siah2 contributes to the development of MCT-induced PAH by destabilizing Lats1/2 and subsequently stimulating YAP activation. Inhibition of Siah2 or proteasome alleviates pulmonary arterial remodeling through inactivation of YAP, indicating Siah2 ubiquitin ligase as a novel target might have potential value in the management of PAH.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Monocrotalina/farmacologia , Proteínas Nucleares/fisiologia , Ubiquitina-Proteína Ligases/fisiologia , Remodelação Vascular/efeitos dos fármacos , Animais , Proteínas Reguladoras de Apoptose/fisiologia , Immunoblotting , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiologia , /fisiopatologia , Ratos , Ratos Sprague-Dawley , Remodelação Vascular/fisiologia
5.
Life Sci ; 242: 117225, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31881229

RESUMO

AIMS: Data concerning the influence of statin lipophilicity on the myotoxic and pleiotropic effects of statins is conflicting, and mechanistic head-to-head comparison studies evaluating this parameter are limited. In order to address the disparity, this mechanistic investigation aimed to assess the effects of two short-acting statins with different lipophilic indices on skeletal, cardiac and vascular smooth muscle physiology. MATERIALS AND METHODS: Young female Wistar rats were randomised to simvastatin (80 mg kg-1 day-1), pravastatin (160 mg kg-1 day-1) or control treatment groups. Changes in functional muscle performance were assessed, as well as mRNA levels of genes relating to atrophy, hypertrophy, mitochondrial function and/or oxidative stress. KEY FINDINGS: There were no significant differences in the mRNA profiles of isolated skeletal muscles amongst the treatment groups. In terms of skeleletal muscle performance, simvastatin reduced functionality but treatment with pravastatin significantly improved force production. Rodents given simvastatin demonstrated comparable myocardial integrity to the control group. Conversely, pravastatin reduced left ventricular action potential duration, diastolic stiffness and Mhc-ß expression. Pravastatin improved endothelium-dependent relaxation, particularly in muscular arteries, but this effect was absent in the simvastatin-treated rats. The responsiveness of isolated blood vessels to noradrenaline also differed between the statin groups. The findings of this study support that the effects of statins on skeletal, cardiac and vascular smooth muscle vary with their lipophilic indices. SIGNIFICANCE: The results of this work have important implications for elucidating the mechanisms responsible for the myotoxic and pleiotropic effects of statins.


Assuntos
Coração/efeitos dos fármacos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Músculo Esquelético/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Pravastatina/farmacologia , Sinvastatina/farmacologia , Animais , Feminino , Microeletrodos , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/metabolismo , Músculo Liso Vascular/metabolismo , Miocárdio/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcriptoma/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos
6.
Life Sci ; 239: 117034, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31697949

RESUMO

AIMS: Although the functional importance of N6-methyladenosine (m6A) in various fundamental bioprocesses are well known, its effect on vascular calcification is not well studied. We investigated the role of methyltransferase-like 14 (METTL14), an m6A methylase, in vascular calcification. MAIN METHODS: We used clinical human samples as well as rat models and primary human artery smooth muscle cell (HASMC) cultures to study the functional role of m6A and METTL14 in vascular calcification and in HASMCs. We modulated the expression of METTL14 using siRNAs (in vitro) to study its function in regulating HASMCs m6A, osteoblasts induced by indoxyl sulfate. We performed the MeRIP-qPCR assays to map and validate m6A in individual transcripts, controls, and calcific HASMCs. KEY FINDINGS: We discovered that the METTL14 expression increases in calcific arteries and in HASMCs induced by indoxyl sulfate, thereby increasing the m6A level in RNA and decreasing the vascular repair function. Decreasing the expression of METTL14 in calcified arteries attenuated the indoxyl sulfate-induced increase in m6A and decrease in HASMCs calcification. We performed the methylation activity of METTL14, which selectively methylates vascular osteogenic transcripts, thereby promoting their degradation and improving their protein expression induced by indoxyl sulfate. Moreover, we demonstrated that the METTL14 de-expression in HASMCs models of calcification decreased the calcification and enhanced the vascular repair function. SIGNIFICANCE: Collectively, our results demonstrated the functional importance of METTL14-dependent vascular m6A methylome in vascular functions during calcification and provided a novel mechanistic insight to the therapeutic mechanisms of METTL14.


Assuntos
Glicoproteínas de Membrana/metabolismo , Metiltransferases/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Calcificação Vascular/genética , Animais , Células Cultivadas , Feminino , Glucuronidase/metabolismo , Humanos , Indicã , Masculino , Glicoproteínas de Membrana/genética , Metilação , Metiltransferases/genética , Metiltransferases/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Proteínas do Tecido Nervoso/genética , Osteogênese/efeitos dos fármacos , Osteogênese/genética , Ratos , Ratos Sprague-Dawley , Calcificação Vascular/induzido quimicamente
7.
J Food Sci ; 84(12): 3573-3583, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31762036

RESUMO

Vascular smooth muscle cells (VSMCs) excessive migration, a basic change of pathological intimal thickening, can lead to serious cardiovascular diseases such as atherosclerosis, myocardial infarction, and stroke. Ligustilide (LIG), the main active ingredient of angelica volatile oil, has been demonstrated to exert protective effects on the cardiovascular and cerebrovascular, circulatory system, and immune function. However, whether it protects against intimal thickening and VSMCs excessive migration and its underlying mechanism remains largely unknown. The aim of this study is to investigate the effect of LIG on VSMCs migration and its underlying mechanism. The protective effect of LIG on VSMCs excessive migration was assessed using an atherosclerotic spontaneously hypertensive rat model and an angiotensin II (AngII)-induced VSMCs migration model. The results showed that LIG exerted a protective effect against pathological intimal thickening as demonstrated by decreasing VSMCs migration in vivo and in vitro. In vivo, intimal thickening and VSMCs migration were inhibited and LIG performed a suppressive effect on the expression of c-Myc protein while enhanced phenotypic transformation related proteins α-SMA expression. Meanwhile, the administration of LIG significantly lowered the blood pressure and blood lipids level in atherosclerotic spontaneously hypertensive rats. In vitro, LIG suppressed AngII-induced VSMCs migration and downregulated the expression of migration related protein c-Myc, MMP2, ROCK1, ROCK2, p-JNK, and JNK. These findings suggested the protective effect of LIG on VSMCs migration was associated with the decrement of c-Myc/MMP2 signaling pathway and ROCK-JNK signaling pathway. Thus, LIG may serve as a novel therapeutic agent for preventing cardiovascular disease.


Assuntos
4-Butirolactona/análogos & derivados , Aterosclerose/tratamento farmacológico , Aterosclerose/fisiopatologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , 4-Butirolactona/administração & dosagem , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Humanos , Masculino , Metaloproteinase 2 da Matriz/genética , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Quinases Associadas a rho/genética , Quinases Associadas a rho/metabolismo
8.
Life Sci ; 238: 116876, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31655194

RESUMO

AIMS: Adiponectin (APN) is a protein hormone secreted mainly by adipose tissue that exhibits biological functions such as anti-inflammatory, anti-atherosclerotic, anti-apoptotic, hearing-protective and microcirculation-regulating functions. In this study, we explored whether APN could attenuate damage caused by CoCl2-induced hypoxic conditions in smooth muscle cells (SMCs) of the spiral modiolar artery (SMA). MAIN METHODS: We first cultured and identified primary SMCs of the SMA. Afterward, the SMCs were pre-treated with APN and then stimulated with CoCl2. KEY FINDINGS: Compared with the control group, the group treated with CoCl2 for 24 h exhibited significantly decreased cell viability, significantly increased apoptosis rates and Malondialdehyde (MDA) levels, and decreased Superoxide Dismutase (SOD) activity. In addition, the expression levels of Bax and cleaved caspase-3 were upregulated, while those of Bcl2 were downregulated evidently. Compared with the CoCl2 group, the group pre-treated with APN before receiving CoCl2 treatment had increased cell viability and SOD activity but decreased MDA levels and apoptosis rates. The expression levels of Bcl2, p-AMPKα and Cx43 were evidently increased, while those of Bax and cleaved caspase-3 were decreased, in the group pre-treated with APN compared to the CoCl2 group. The protective effect of APN was blocked by the AMPK inhibitor Compound C and the Cx43 inhibitor Gap19. SIGNIFICANCE: Our study demonstrated that APN protected SMCs against CoCl2-induced hypoxic injury via the AMPK signalling pathway and regulated the expression of Cx43 in cells. Therefore, APN might be a promising treatment for diseases related to circulation disturbances of the inner ear.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adiponectina/farmacologia , Apoptose/efeitos dos fármacos , Artérias/efeitos dos fármacos , Cóclea/irrigação sanguínea , Conexina 43/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Animais , Antimutagênicos/toxicidade , Artérias/metabolismo , Artérias/patologia , Cobalto/toxicidade , Regulação da Expressão Gênica/efeitos dos fármacos , Cobaias , Hipóxia/induzido quimicamente , Hipóxia/tratamento farmacológico , Hipóxia/metabolismo , Hipóxia/patologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Espécies Reativas de Oxigênio
9.
Rev Cardiovasc Med ; 20(3): 139-151, 2019 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-31601088

RESUMO

Effective therapy of hypertension represents a key strategy for reducing the burden of cardiovascular disease and its associated mortality. The significance of voltage dependent L-type Ca²âº channels to Ca²âº influx, and of their regulatory mechanisms in the development of heart disease, is well established. A wide variety of L-type Ca²âº channel inhibitors and Ca²âº antagonists have been found to be beneficial not only in the treatment of hypertension, but also in myocardial infarction and heart failure. Over the past two decades, another class of Ca²âº channel - the voltage independent store-operated Ca²âº channel - has been implicated in the regulation and fine tuning of Ca²âº entry in both cardiac and smooth muscle cells. Store-operated Ca²âº channels are activated by the depletion of Ca²âº stores within the endoplasmic/sarcoplasmic reticulum, or by low levels of cytosolic Ca²âº, thereby facilitating agonist-induced Ca²âº influx. Store-operated Ca²âº entry through this pivotal pathway involves both stromal interaction molecule (STIM) and Orai channels. Different degrees of changes in these proteins are considered to promote Ca²âº entry and hence contribute to the pathogenesis of cardiovascular dysfunction. Several blockers of store-operated Ca²âº channels acting at the level of both STIM and Orai channels have been shown to depress Ca²âº influx and lower blood pressure. However, their specificity, safety, and clinical significance remain to be established. Thus, there is an ongoing challenge in the development of selective inhibitors of store-operated Ca²âº channels that act in vascular smooth muscles for the improved treatment of hypertension.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/uso terapêutico , Canais de Cálcio Ativados pela Liberação de Cálcio/antagonistas & inibidores , Hipertensão/tratamento farmacológico , Músculo Liso Vascular/efeitos dos fármacos , Moléculas de Interação Estromal/antagonistas & inibidores , Vasodilatadores/uso terapêutico , Animais , Anti-Hipertensivos/efeitos adversos , Bloqueadores dos Canais de Cálcio/efeitos adversos , Canais de Cálcio Tipo L/efeitos dos fármacos , Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio Ativados pela Liberação de Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Humanos , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Moléculas de Interação Estromal/metabolismo , Resultado do Tratamento , Vasodilatadores/efeitos adversos
10.
Life Sci ; 237: 116943, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31604109

RESUMO

AIMS: The purpose of this study was to investigate the therapeutic effect of artemisinin (ART) on atherosclerosis and explore the molecular mechanisms involved by RNA sequencing (RNA-Seq). MAIN METHODS: Eight-week-old male ApoE-/- mice were treated with ART for eight weeks. Atherosclerotic lesion sizes were determined by Oil Red O staining, and RNA-Seq was used to detect the profile of differentially expressed genes following the administration of ART. The expressions of contractile phenotypic markers were detected by western blot and qRT-PCR, and the ability of the MOVAS cells to migrate and proliferate were assessed using the wound healing and CCK8 assays. KEY FINDINGS: Artemisinin treatment significantly reduced plaque area in the ApoE-/- mice and increased the expression of contractile phenotypic markers. RNA-Seq of aorta tissue revealed a distinct change in gene expression patterns after the mice were treated with ART. Our bioinformatics analysis demonstrated that the most prominently enriched pathway was a set of genes involved in vascular smooth muscle contractile function. Using an in vitro cell model, we demonstrated that ART could effectively reverse PDGF-activated MOVAS migration and proliferation, and elevate the level of proteins involved in the contractile phenotype. SIGNIFICANCE: We provide in vivo and in vitro evidence supporting a role for ART in the suppression of atherosclerosis, partly through the inhibition of vascular smooth muscle cell phenotype switching to a de-differentiated phenotype. These data further advances our understanding for a potential role for ART and suggests that ART is an excellent candidate for the treatment of atherosclerosis.


Assuntos
Antimaláricos/farmacologia , Apolipoproteínas E/fisiologia , Artemisininas/farmacologia , Aterosclerose/prevenção & controle , Proliferação de Células , Modelos Animais de Doenças , Músculo Liso Vascular/citologia , Animais , Aterosclerose/etiologia , Aterosclerose/patologia , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Fenótipo , Transdução de Sinais
11.
J Biosci ; 44(4)2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31502564

RESUMO

Vascular calcification is a common problem in the elderly with diabetes, heart failure and end-stage renal disease. The differentiation of vascular smooth muscle cells (VSMCs) into osteoblasts is the main feature, but the exact mechanism remains unclear. It is not clear whether adiponectin (APN) affects osteogenic differentiation of VSMCs. This study aims to explore the effect of APN on vascular calcification by using a cell model induced by beta-glycerophosphate (beta-GP). VSMCs were isolated and treated with beta-GP and APN in this study. The alkaline phosphatase (ALP) activity and expression levels of Runx2, BMP-2, collagen type I and osteocalcin were determined. The expression levels of STAT3 and p-STAT3 in nucleus and cytoplasm of VSMCs were analyzed. The results showed that APN significantly inhibited the expression of ALP, Runx2, BMP-2, collagen I, osteocalcin and the formation of the mineralized matrix in VSMCs induced by beta-GP. APN reduces the osteogenic differentiation of VSMCs induced by beta-GP and down-regulates the expression of the osteogenic transcription factor osterix by inhibiting STATS3 phosphorylation and nuclear transport. APN may be one of the potential candidates for clinical treatment of vascular calcification.


Assuntos
Adiponectina/genética , Osteogênese/genética , Fator de Transcrição STAT3/genética , Calcificação Vascular/genética , Animais , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Glicerofosfatos/farmacologia , Humanos , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Camundongos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Osteogênese/efeitos dos fármacos , RNA/genética , Fator de Transcrição STAT3/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição Sp7/genética , Calcificação Vascular/induzido quimicamente , Calcificação Vascular/patologia
12.
Int J Mol Sci ; 20(18)2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31500240

RESUMO

Omega-3 fatty acids are important to pregnancy and neonatal development and health. One mechanism by which omega-3 fatty acids exert their protective effects is through serving as substrates for the generation of specialized pro-resolving lipid mediators (SPM) that potently limit and resolve inflammatory processes. We recently identified that SPM levels are increased in maternal blood at delivery as compared to umbilical cord blood, suggesting the placenta as a potential site of action for maternal SPM. To explore this hypothesis, we obtained human placental samples and stained for the SPM resolvin D2 (RvD2) receptor GPR18 via immunohistochemistry. In so doing, we identified GPR18 expression in placental vascular smooth muscle and extravillous trophoblasts of the placental tissues. Using in vitro culturing, we confirmed expression of GPR18 in these cell types and further identified that stimulation with RvD2 led to significantly altered responsiveness (cytoskeletal changes and pro-inflammatory cytokine production) to lipopolysaccharide inflammatory stimulation in human umbilical artery smooth muscle cells and placental trophoblasts. Taken together, these findings establish a role for SPM actions in human placental tissue.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Músculo Liso Vascular/citologia , Receptores Acoplados a Proteínas-G/genética , Trofoblastos/citologia , Adulto , Células Cultivadas , Ácidos Graxos Ômega-3/farmacologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Idade Materna , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Placenta/citologia , Placenta/efeitos dos fármacos , Placenta/metabolismo , Gravidez , Receptores Acoplados a Proteínas-G/metabolismo , Trofoblastos/efeitos dos fármacos , Trofoblastos/metabolismo , Adulto Jovem
13.
Molecules ; 24(18)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31489892

RESUMO

Vascular smooth muscle cells (VSMCs) loaded with lipid droplets (LDs) are markers of atherosclerosis. In this disease, inflammatory Group IIA-secreted phospholipase A2s (GIIA sPLA2s) are highly expressed in VSMCs, but their actions in these cells are unknown. Here, we investigated the ability of myotoxin III (MT-III), an ophidian GIIA sPLA2 sharing structural and functional features with mammalian GIIA sPLA2s, to induce LD formation and lipid metabolism factors involved in this effect. Modulation of VSMC phenotypes by this sPLA2 was also evaluated. Incubation of VSMCs with MT-III significantly increased the number of LDs. MT-III upregulated scavenger receptor type 1 (SR-A1) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) protein expression and enhanced acetylated-low density lipoprotein (acLDL) uptake by VSMCs, revealing the ability of a GIIA PLA2 to modulate scavenger receptor activities. MT-III induced translocation and protein expression of PPAR-γ and -ß/δ. Inhibition of peroxisome proliferator-activated receptors (PPARs) and diacylglycerol O-acyltransferase (DGAT) and acyl-CoA:cholesterolacyltransferase (ACAT) enzymes abrogated MT-III-induced LD formation. Moreover, in response to MT-III, VSMCs acquired phagocytic activity and expressed macrophage markers CD68 and MAC-2. In conclusion, MT-III is able to stimulate VSMCs and recruit factors involved in lipid uptake and metabolism, leading to the formation of VSMC-derived foam cells with acquisition of macrophage-like markers and functions.


Assuntos
Transdiferenciação Celular/efeitos dos fármacos , Células Espumosas/citologia , Fosfolipases A2 do Grupo II/farmacologia , Músculo Liso Vascular/citologia , Animais , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Fenótipo , Ratos , Receptores Depuradores Classe A/metabolismo , Receptores Depuradores Classe E/metabolismo
14.
J Biomed Sci ; 26(1): 68, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492153

RESUMO

BACKGROUND: Increasing evidence suggests that high glucose (HG) causes abnormalities in endothelial and vascular smooth muscle cell function (VSMC) and contributes to atherosclerosis. Receptor for advanced glycation end-products (RAGE) has been linked to the pathogenesis of both the macrovascular and microvascular complications of diabetes. Cilostazol is used to treat diabetic vasculopathy by ameliorating HG-induced vascular dysfunction. OBJECTIVES: In this study, we investigated whether the cilostazol suppression of HG-induced VSMC dysfunction is through RAGE signaling and its possible regulation mechanism. METHOD: We investigated the effect of HG and cilostazol on RAGE signaling in A7r5 rat VSMCs. Aortic tissues of streptozotocin (STZ) diabetic mice were also collected. RESULTS: Aortic tissue samples from the diabetic mice exhibited a significantly decreased RAGE expression after cilostazol treatment. HG increased RAGE, focal adhesion kinase (FAK), matrix metalloproteinase-2 (MMP-2), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expressions, and was accompanied with increased reactive oxygen species (ROS), cell proliferation, adhesion and migration. Cilostazol significantly reversed HG-induced RAGE, ROS, downstream gene expressions and cell functions. RAGE knockdown significantly reversed the expressions of HG-induced vasculopathy related gene expressions and cell functions. Cilostazol with RAGE knockdown had additive effects on downstream ERK/NF-κB signaling pathways, gene expressions and cell functions of A7r5 rat VSMCs in HG culture. CONCLUSIONS: Both in vitro and in vivo experimental diabetes models showed novel signal transduction of cilostazol-mediated protection against HG-related VSMC dysfunction, and highlighted the involvement of RAGE signaling and downstream pathways.


Assuntos
Cilostazol/farmacologia , Angiopatias Diabéticas/tratamento farmacológico , Glucose/efeitos adversos , Músculo Liso Vascular/efeitos dos fármacos , Inibidores da Fosfodiesterase 3/farmacologia , Transdução de Sinais , Animais , Sistema de Sinalização das MAP Quinases , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Músculo Liso Vascular/fisiopatologia , NF-kappa B/metabolismo , Ratos , Receptor para Produtos Finais de Glicação Avançada/metabolismo
15.
Int J Med Sci ; 16(8): 1149-1156, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31523178

RESUMO

Background Sepsis, a leading cause of death in intensive care units, is generally associated with vascular dysfunction. However, its pathophysiological process has not been fully clarified, lacking in-depth knowledge of its pathophysiological process may hinder the improvement of diagnosis and therapy for sepsis. Hence, as the key parts of the vascular wall, the interaction between endothelial cells (ECs) and smooth muscle cells (SMCs) under septic situation need to be further studied. Methods ECs and SMCs were co-cultured using Transwell plates. Lipopolysaccharide (LPS) was used to induce sepsis. A scratch-wound assay was used to assess cell migration, and western blotting was used to assess the level of redifferentiation of SMCs as well as the expression of PDGFR-ß and IQGAP1. Results Co-culture with ECs reduced the redifferentiation of SMCs induced by LPS (10 µg/ml), which was characterized by increased migration ability and decreased expression of contractile proteins (e.g., SM22 and α-SMA). The production of TNF-α could decrease the level of PDGFR-ß in SMCs. Treatment of SMCs with the PDGFR-ß inhibitor imatinib (5 µM) was able to counteract LPS-induced SMC redifferentiation and reduce IQGAP1 protein expression, especially when SMCs were co-cultured with ECs. Conclusion The phenotype of vascular SMCs co-cultured with ECs was modulated by IQGAP1 through the PDGFR-ß pathway, which may lead to vascular remodeling and homeostasis in LPS-induced intravascular injury. This pathway could be a novel target for the treatment of vascular damage.


Assuntos
Músculo Liso Vascular/citologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Proteínas Ativadoras de ras GTPase/metabolismo , Técnicas de Cocultura , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Humanos , Lipopolissacarídeos/toxicidade , Músculo Liso Vascular/efeitos dos fármacos , Fenótipo , Sepse/metabolismo , Sepse/patologia , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismo
16.
Food Chem Toxicol ; 134: 110804, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31505234

RESUMO

OBJECTIVE: To investigate the role of inflammatory response, oxidative damage and changes of ATP-sensitive potassium channels (sKATP) in basilar artery (BA) smooth muscle cells (SMCS) of rabbits in subarachnoid hemorrhage (SAH) model. METHODS: Time course studies on inflammatory response by real-time PCR, oxidative process and function of isolated basilar artery after SAH in New Zealand White rabbits were performed. Basilar artery smooth muscle cells (BASMCs) in each group were obtained and whole-cell patch-clamp technique was applied to record cell membrane capacitance and KATP currents. The morphologies of basal arteries were analyzed. Protective effect of shikonin were also determine by same parameters. RESULTS: Inflammatory cytokines levels were highest at 24h compare to 72h after SAH whereas the oxidative damage and cell death marker were at highest peak at 72h. Oxidative damage peak coincided with significant alterations in cell membrane capacitance, KATP currents and morphological changes in basilar arteries. Shikokin pretreatment attenuated early inflammatory response at 24h and associated oxidative damage at 72h. Finally, shikonin attenuated morphological changes in basilar arteries and dysfunction. CONCLUSION: Currents of ATP-sensitive potassium channels in basilar smooth muscle cells decreased after SAH by putative oxidative modification from immediate inflammatory response and can be protected by shikonin pretreatment.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Artéria Basilar/efeitos dos fármacos , Canais KATP/fisiologia , Músculo Liso Vascular/efeitos dos fármacos , Naftoquinonas/farmacologia , Hemorragia Subaracnóidea/patologia , Animais , Artéria Basilar/metabolismo , Artéria Basilar/patologia , Citocinas/metabolismo , Feminino , Mediadores da Inflamação/metabolismo , Masculino , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Estresse Oxidativo , Técnicas de Patch-Clamp , Coelhos , Hemorragia Subaracnóidea/imunologia , Hemorragia Subaracnóidea/metabolismo
17.
J Physiol Pharmacol ; 70(2)2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31443091

RESUMO

The proliferation of vascular smooth muscle cells plays a crucial role in pathogenesis of cardiovascular disease. The principal objective of this study was to determine the effects of Ojeoksan (OJS) on human aortic smooth muscle cell (HASMC) proliferation induced by tumor necrosis factor α (TNF-aα). Thymidine incorporation after TNF-α treatment was increased and this effect was inhibited significantly by OJS treatment. HASMC proliferation and migration by kinetic live cell imaging were also reduced by treatment with OJS. TNF-α induced the expression of cyclins/cyclin-dependent kinases (CDKs) and reduced the expression of p21waf1/cip1/p27kip1. However, OJS also attenuated the expression of TNF-α-induced cell-cycle regulatory proteins. The results of Western blot analysis demonstrated that the TNF-α treated HASMC secreted gelatinases, probably including MMP-2/-9, which may be involved in the invasion and migration of HASMC. Additionally, OJS suppressed the mRNA expression levels of matrix metalloproteinase-2/-9 (MMP-2/-9) in a dose-dependent manner. OJS inhibited the production of TNF-α-induced hydrogen peroxide (H2O2) and the formation of DCF-sensitive intracellular reactive oxygen species (ROS). Further, OJS suppressed the nuclear translocation and phosphorylation of inhibitor of kappa B-α (IκB-α) of nuclear factor κB (NF-κB) under TNF-α conditions. Our results demonstrate that OJS exerts inhibitory effects on TNF-α-induced HASMC proliferation and migration, suggesting the involvement of the inhibition of both MMP-2 and MMP-9 expressions, and the downregulation of ROS/NF-κB signaling. Thus, herbal decoction OJS may be a possible therapeutic approach to the inhibition of cardiovascular disease including atherosclerosis.


Assuntos
Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Aorta/efeitos dos fármacos , Aorta/metabolismo , Células Cultivadas , Inibidor de Quinase Dependente de Ciclina p27/metabolismo , Regulação para Baixo/efeitos dos fármacos , Humanos , Peróxido de Hidrogênio/farmacologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Fosforilação/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo
18.
Kidney Blood Press Res ; 44(4): 643-655, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31430759

RESUMO

AIMS: The current study was conducted with the central objective of investigating the expression of microRNA-145 (miR-145) in renal vascular lesions (RVLs) in juvenile lupus nephritis (JLN) and its possible mechanism. METHODS: The clinical data of 49 JLN patients confirmed by renal biopsy were collected and followed by grouping according to the RVLs score after hematoxylin-eosin staining: mild, moderate, and severe groups. In situ hybridization was used to detect the expression of miR-145 in renal vessels which was then being compared among different RVLs groups. Up-LV-miR-145 and LV-miR-NC lentiviral vectors were constructed and transfected into human vascular smooth muscle cells (HVSMCs), respectively. After HVSMCs were treated with 10.0 µg/L platelet-derived growth factor (PDGF)-BB for 24 h, the proliferation, migration, and apoptosis of endothelial cells were detected by MTT, Transwell assay, and flow cytometry, respectively. Western blot was used to detect expression of alpha-smooth muscle actin (α-SM-actin) and osteopontin (OPN). RESULTS: The expression of miR-145 in renal vascular cells was statistically significant. The higher the inner membrane ratio, the lesser the miR-145 expression. After treatment with PDGF-BB, expression of miR-145 in HVSMCs decreased, proliferation and migration ability enhanced, apoptosis decreased, α-SM-actin decreased, and OPN increased. The proliferation and migration ability of HVSMCs in the LV-miR-145 group suppressed, apoptosis enhanced, α-SM-actin increased, and OPN decreased. CONCLUSIONS: Our study revealed that miR-145 expression decreased with the increase of vascular damage. miR-145 can inhibit proliferation, migration, and differentiation phenotypic transformation of HVSMCs induced by PDGF-BB. miR-145 may be involved in the pathogenesis of RVLs and may be a new target for treatment of RVLs in lupus nephritis.


Assuntos
Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/patologia , MicroRNAs/farmacologia , Adolescente , Apoptose/efeitos dos fármacos , Becaplermina/farmacologia , Vasos Sanguíneos/citologia , Vasos Sanguíneos/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Criança , Pré-Escolar , Feminino , Humanos , Rim/irrigação sanguínea , Nefrite Lúpica/etiologia , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Transfecção
19.
Life Sci ; 233: 116745, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31404524

RESUMO

Hypertension is one of the major risk factors for cardiovascular disease worldwide and is striking more young people, which is characterized by impaired vascular endothelial function. To find the functional lncRNAs associated with hypertension, high throughput lncRNA microarray were used to analyze expression profile of the lncRNAs in the aortic vascular endothelial cells (VECs) of spontaneously hypertensive rats (SHRs). The tail vein injection of siRNA was used to study the influence of lncRNA AK094457 inhibition on endothelial function in vivo. In vitro, endothelial function was studied in endothelial cells transfected with lncRNA AK094457-overexpressed vectors and siRNAs. pPPARγ and iNOS protein levels were detected with Western blot. Elisa assay was used to analyze the secretion of AngII, ET-1, ROS and LDH level. The nitrite/nitrate (NO2-/NO3-) concentration was measured using a colorimetric assay. LncRNA AK094457 was a most upregulated lncRNA in SHRs. It is showed that downregulation of AK094457 significantly reduced rat arterial pressure, increased activation of endothelial PPARγ, and suppressed serum contents of AngII and NO in vivo. Furthermore, results from gain-and-loss of function in primary aortic endothelial cells indicated that AK094457 negatively regulated activation of PPARγ and promoted AngII-mediated endothelial dysfunction, manifested by decreased capacities of cell proliferation and migration, and increased levels of ROS production and LDH release. In conclusion, lncRNA AK094457 is identified as a key regulator in blood pressure and endothelial function, which can increase AngII-induced hypertension and endothelial dysfunction via suppression of PPARγ.


Assuntos
Angiotensina II/toxicidade , Endotélio Vascular/patologia , Hipertensão/patologia , Músculo Liso Vascular/patologia , PPAR gama/antagonistas & inibidores , RNA Longo não Codificante/genética , Vasoconstritores/toxicidade , Animais , Proliferação de Células , Células Cultivadas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/genética , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Ratos , Ratos Endogâmicos SHR , Transdução de Sinais , Remodelação Vascular
20.
Biomed Res Int ; 2019: 8483765, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467913

RESUMO

Intimal hyperplasia is a complex process which contributes to several clinical problems such as atherosclerosis and postangioplasty restenosis. Inhibition of Smad3 expression inhibits intimal thickening. Our previous study has modified biscarbamate cross-linked polyethylenimine derivative (PEI-Et) through PEGylation thus obtained polyethylene glycol-graft-polyethylenimine derivative (PEG-Et 1:1), which has lower cytotoxicity and higher gene transfection efficiency compared with PEI-Et. In this study, PEG-Et 1:1 was employed in Smad3 shRNA (shSmad3) delivery for preventing intimal hyperplasia after vascular injury. It was observed that PEG-Et 1:1 could condense shSmad3 gene into nanoparticles with particle size of 115-168 nm and zeta potential of 3-6 mV. PEG-Et 1:1 displayed remarkably lower cytotoxicity, higher transfection efficiency, and shRNA silencing efficiency than PEI-Et and PEI 25 kDa in vascular smooth muscle cells (VSMCs). Moreover, PEG-Et 1:1/shSmad3 polyplex treatment significantly inhibited collagen, matrix metalloproteinase 1 (MMP1), MMP2 and MMP9 expression, and upregulated tissue inhibitor of metalloproteinase 1 (TIMP1) expression both in vitro and in vivo. Furthermore, intravascular delivery of shSmad3 with PEG-Et 1:1 polyplex efficiently reduced Smad3 expression and inhibited intimal thickening 14 days after vascular injury. Ultimately, this study indicated that PEG-Et 1:1-mediated local delivery of shSmad3 is a promising strategy for preventing intimal thickening.


Assuntos
Espessura Intima-Media Carotídea , Polietilenoimina/farmacologia , Proteína Smad3/genética , Lesões do Sistema Vascular/genética , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Nanopartículas , Plasmídeos , Polietilenoglicóis/química , Polietilenoimina/química , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Coelhos , Proteína Smad3/farmacologia , Transfecção , Lesões do Sistema Vascular/patologia , Lesões do Sistema Vascular/terapia
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