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

RESUMO

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


Assuntos
Alopecia/genética , Encéfalo/irrigação sanguínea , Infarto Cerebral/genética , Serina Peptidase 1 de Requerimento de Alta Temperatura A/genética , Leucoencefalopatias/genética , Mutação , Doenças da Coluna Vertebral/genética , Alopecia/enzimologia , Alopecia/patologia , Animais , Apoptose , Células Cultivadas , Infarto Cerebral/enzimologia , Infarto Cerebral/patologia , Predisposição Genética para Doença , Serina Peptidase 1 de Requerimento de Alta Temperatura A/metabolismo , Leucoencefalopatias/enzimologia , Leucoencefalopatias/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Fenótipo , Doenças da Coluna Vertebral/enzimologia , Doenças da Coluna Vertebral/patologia
2.
J Agric Food Chem ; 67(46): 12752-12760, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31642668

RESUMO

Atherosclerosis, the major risk of cardiovascular events, is a chronic vascular inflammatory disease. Pterostilbene is a naturally occurring dimethylated analogue of resveratrol and has recently been demonstrated to be beneficial against cardiovascular diseases. However, the underlying mechanisms of pterostilbene on atherosclerosis remain elusive. Experimental atherosclerosis was induced by a high-fat diet (HFD) in apolipoprotein E knockout (ApoE-/-) mice. Pterostilbene was administered intragastrically for 16 weeks. We found that pterostilbene significantly attenuated thoracic and abdominal atherosclerotic plaque formation in HFD-fed ApoE-/-mice, accompanied by modulated lipid profiles and reduced production of proinflammatory cytokines (including IL-6, IFN-γ, and TNF-α). In addition, pterostilbene restored vascular redox balance in thoracic and abdominal aorta, evidenced by enhanced catalase (CAT) expression and activities, and decreased malondialdehyde and H2O2 production. Notably, pterostilbene specifically induced CAT expression and activities in the vascular smooth muscle cells (VSMCs) of thoracic and abdominal aorta. In vitro, pterostilbene markedly promoted the expression and activity of CAT and decreased ox-low-density lipoprotein (LDL)-mediated VSMC proliferation and intracellular H2O2 production, which was abolished by CAT siRNA knockdown or inhibition. Pterostilbene-induced CAT expression was associated with inhibition of Akt, PRAS40, and GSK-3ß signaling activation and upregulation of PTEN. Our data clearly demonstrated that pterostilbene exerted an antiatherosclerotic effect by inducing CAT and modulating the VSMC function.


Assuntos
Aterosclerose/tratamento farmacológico , Catalase/metabolismo , Músculo Liso Vascular/enzimologia , Estilbenos/administração & dosagem , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Catalase/genética , Glicogênio Sintase Quinase 3 beta/genética , Glicogênio Sintase Quinase 3 beta/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Interferon gama/genética , Interferon gama/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Lipoproteínas LDL/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Oxirredução
3.
J Vasc Res ; 56(3): 117-128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31085922

RESUMO

Previous studies have shown that metformin (MET) prevents experimental pulmonary arterial hypertension (PAH) and that activation of autophagy is involved in the development of pulmonary vascular remodeling. However, the mechanism of how MET inhibits autophagy and reverses pulmonary vascular remodeling is still unclear. The objective of the present study was to investigate the role of autophagy in MET-induced hypoxia PAH protection and the underlying mechanisms. To examine the effects of MET on hypoxia, we treated rats with MET (100 mg/kg/day) after 3 weeks of hypoxia. Hemodynamic changes, weight of the right ventricle/left ventricle plus septum (RV/LV+S) ratio, and lung morphological features were examined after 3 weeks. In addition, alpha smooth muscle actin (α-SMA), p62, and PCNA were assessed by immunofluorescence and immunohistochemistry staining. BECN-1, LC3B, p62, and activation of adenosine monophosphate-activated protein kinase (AMPK) were analyzed by Western blotting. Cell proliferation was detected using the Cell Counting Kit-8 (CCK-8) and the 5-ethynyl-2'-deoxyuridine staining kit assay. Hypoxia induced increases in right ventricular systolic pressure and the RV/LV+S ratio, which were attenuated by MET treatment. MET also inhibited hypoxia-induced pulmonary vascular remodeling, collagen deposition, proliferation of pulmonary arterial smooth muscle cells, elevation of BECN-1 and the LC3B-II/-I ratio, and downregulation of p62. Further studies found that this process was mediated by inhibition of autophagy and activation of the AMPK signaling pathway.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Autofagia/efeitos dos fármacos , Metformina/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Artéria Pulmonar/efeitos dos fármacos , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Progressão da Doença , Ativação Enzimática , Humanos , Hipóxia/complicações , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , /etiologia , Artéria Pulmonar/enzimologia , Artéria Pulmonar/patologia , Ratos Wistar , Transdução de Sinais , Remodelação Vascular/efeitos dos fármacos , Função Ventricular Direita/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
4.
J Vasc Res ; 56(3): 109-116, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31085923

RESUMO

BACKGROUND/AIMS: Soluble guanylate cyclase (sGC) exists as reduced, oxidized, and heme-free forms. Currently, it is unclear whether endovascular mechanical stenosis has an impact on vascular tone control by drugs targeting sGC, namely cGMP generators. METHODS: Pharmacological responses to acidified sodium nitrite (reduced sGC stimulant) and BAY 60-2770 (oxidized/heme-free sGC stimulant) were studied in balloon-injured rat carotid arteries at several time points. In addition, sGC expression was detected by immunohistochemistry. RESULTS: At 1 day after injury, acidified sodium nitrite-induced relaxation was attenuated in the injured artery, whereas BAY 60-2770-induced relaxation was augmented. Similar attenuation of response to acidified sodium nitrite was seen at 7 and 14 days after injury. On the other hand, the augmentation of response to BAY 60-2770 disappeared at 7 and 14 days after injury. At 1 day after injury, the immunohistochemical expression pattern of sGC in the smooth muscle layer of the injured artery was not different from that of the uninjured artery. However, in the injured artery, the intensity of sGC staining was weak at 7 and 14 days after injury. CONCLUSION: Balloon injury alters vascular responsiveness to cGMP generators, which seems to be associated with the form and/or expression of sGC.


Assuntos
Benzoatos/farmacologia , Compostos de Bifenilo/farmacologia , Lesões das Artérias Carótidas/tratamento farmacológico , GMP Cíclico/metabolismo , Ativadores de Enzimas/farmacologia , Hidrocarbonetos Fluorados/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Doadores de Óxido Nítrico/farmacologia , Nitrito de Sódio/farmacologia , Guanilil Ciclase Solúvel/metabolismo , Vasodilatação/efeitos dos fármacos , Angioplastia com Balão , Animais , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/enzimologia , Artérias Carótidas/patologia , Lesões das Artérias Carótidas/enzimologia , Lesões das Artérias Carótidas/patologia , Modelos Animais de Doenças , Ativação Enzimática , Masculino , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Ratos Sprague-Dawley , Sistemas do Segundo Mensageiro , Fatores de Tempo
5.
Pharmazie ; 74(3): 168-174, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30961684

RESUMO

Inflammation and vascular smooth muscle cells (VSMCs) play key roles in the development of many cardiovascular diseases (CVDs). Although vitamin D decreases the risks of inflammation related diseases including CVDs, the links between vitamin D, VSMCs and vascular inflammation remained unclear. In this study, we investigated the anti-inflammatory effect and signaling pathways of vitamin D in lipopolysaccharide (LPS)-induced VSMCs. 1,25(OH)2D3 treatment inhibited the significant upregulation of COX-2, PGE2, TNF-α and IL-6 and p38 phosphorylation induced by LPS in A10 cells. Blocking p38 signaling attenuated the inhibitory effect of 1,25(OH)2D3 on the upregulation of COX-2 and phosphorylation of p38. These results indicate 1,25(OH)2D3 suppresses inflammatory response in LPS-induced VSMCs through p38 MAPK signaling pathway.


Assuntos
Calcitriol/farmacologia , Lipopolissacarídeos/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Células Cultivadas , Ciclo-Oxigenase 2/biossíntese , Ciclo-Oxigenase 2/metabolismo , Inibidores de Ciclo-Oxigenase 2/farmacologia , Dinoprostona/antagonistas & inibidores , Dinoprostona/biossíntese , Dinoprostona/metabolismo , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/enzimologia , Inflamação/patologia , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , NF-kappa B/metabolismo , Fosforilação , Ratos , Fator de Necrose Tumoral alfa/metabolismo
6.
Nutr Metab Cardiovasc Dis ; 29(6): 621-632, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31005375

RESUMO

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


Assuntos
Lesões das Artérias Carótidas/enzimologia , Diabetes Mellitus Experimental/enzimologia , MicroRNAs/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Remodelação Vascular , Animais , Artérias Carótidas/enzimologia , Artérias Carótidas/patologia , Lesões das Artérias Carótidas/genética , Lesões das Artérias Carótidas/patologia , Movimento Celular , Proliferação de Células , Células Cultivadas , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Colágenos Fibrilares/metabolismo , Masculino , MicroRNAs/genética , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Neointima , Ratos Sprague-Dawley , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo
7.
J Vasc Surg ; 69(5): 1581-1589.e1, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31010523

RESUMO

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


Assuntos
Angioplastia com Balão/instrumentação , Proliferação de Células/efeitos dos fármacos , Stents Farmacológicos , Inibidores Enzimáticos/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Compostos Orgânicos/farmacologia , Proteínas Proto-Oncogênicas c-yes/metabolismo , Proteínas rho de Ligação ao GTP/antagonistas & inibidores , Angioplastia com Balão/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Artérias Carótidas/efeitos dos fármacos , Artérias Carótidas/enzimologia , Artérias Carótidas/patologia , Células Cultivadas , Constrição Patológica , Masculino , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Neointima , Proteínas Proto-Oncogênicas c-yes/genética , Coelhos , Ratos , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo , Proteínas rho de Ligação ao GTP/metabolismo
8.
Mol Med Rep ; 19(5): 3767-3774, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896798

RESUMO

The contractility of vascular smooth muscle cells (VSMCs) controls the lumen diameter of vessels, thus serving a role in regulating blood pressure and organ blood flow. Although arginases are known to have numerous effects in the biological activities of VSMCs, the effects of arginase II on the constriction of VSMCs has not yet been investigated. When conducting a natural products screen for an inhibitor against arginase, the present study identified that a relatively high concentration of resveratrol (RSV) exhibited arginase inhibitory activity. Therefore, the present study investigated whether RSV could regulate VSMCs contractions and the underlying mechanism. Arginase inhibition by RSV led to an increase in the concentration of the substrate L­Arg and an accompanying increase in the cytosol Ca2+ concentration [(Ca2+)c] in VSMCs. The increased [Ca2+]c induced by RSV and L­Arg treatments resulted in CaMKII­dependent MLC20 phosphorylation. The effects of RSV on VSMCs were maintained even when VSMCs were pre­treated with sirtinol, an inhibitor of Sirt proteins. In a vascular tension assay with de­endothelialized aortic vessels, vasoconstrictor responses, which were measured using phenylephrine (PE), were significantly enhanced in the RSV­ and L­Arg­treated vessels. Therefore, although arginase inhibition has exhibited beneficial effects in various diseases, care is required when considering administration of an arginase inhibitor to patients with vessels endothelial dysfunction as RSV can induce vessel contraction.


Assuntos
Arginase/antagonistas & inibidores , Cálcio/metabolismo , Citosol/metabolismo , Inibidores Enzimáticos/farmacologia , Músculo Liso Vascular/patologia , Resveratrol/farmacologia , Vasoconstrição/efeitos dos fármacos , Animais , Arginina/metabolismo , Células Cultivadas , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/enzimologia , Ratos , Ratos Sprague-Dawley , Vasoconstritores/farmacologia
9.
Microvasc Res ; 124: 43-50, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30853343

RESUMO

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


Assuntos
Proliferação de Células , Proteínas do Citoesqueleto/metabolismo , Hipertensão Pulmonar/enzimologia , MicroRNAs/metabolismo , Proteínas dos Microfilamentos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Oxirredutases/metabolismo , Animais , Células Cultivadas , Proteínas do Citoesqueleto/genética , Modelos Animais de Doenças , Humanos , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/patologia , Hipóxia/complicações , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Proteínas dos Microfilamentos/genética , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Oxirredutases/genética , Artéria Pulmonar/enzimologia , Artéria Pulmonar/patologia , Transdução de Sinais , Remodelação Vascular
10.
Arterioscler Thromb Vasc Biol ; 39(4): 731-740, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30841708

RESUMO

Objective- The objective of this study was to investigate the effect of intravenous maternal sildenafil citrate (SC) administration on vascular function in growth-restricted fetal sheep. Approach and Results- Fetal growth restriction (FGR) results in cardiovascular adaptations that redistribute cardiac output to optimize suboptimal intrauterine conditions. These adaptations result in structural and functional cardiovascular changes, which may underlie postnatal neurological and cardiovascular sequelae. Evidence suggests SC, a potent vasodilator, may improve FGR. In contrast, recent clinical evidence suggests potential for adverse fetal consequence. Currently, there is limited data on SC effects in the developing fetus. We hypothesized that SC in utero would improve vascular development and function in an ovine model of FGR. Preterm lambs (0.6 gestation) underwent sterile surgery for single umbilical artery ligation or sham (control, appropriately grown) surgery to replicate FGR. Ewes received continuous intravenous SC (36 mg/24 h) or saline from surgery until 0.83 gestation. Fetuses were delivered and immediately euthanized for collection of femoral and middle cerebral artery vessels. Vessel function was assessed via in vitro wire myography. SC exacerbated growth restriction in growth-restricted fetuses and resulted in endothelial dysfunction in the cerebral and femoral vasculature, irrespective of growth status. Dysfunction in the cerebral circulation is endothelial, whereas smooth muscle in the periphery is the origin of the deficit. Conclusions- SC crosses the placenta and alters key fetal vascular development. Extensive studies are required to investigate the effects of SC on fetal development to address safety before additional use of SC as a treatment.


Assuntos
Retardo do Crescimento Fetal/induzido quimicamente , Lesões Pré-Natais/induzido quimicamente , Citrato de Sildenafila/toxicidade , Vasodilatadores/toxicidade , Acetilcolina/farmacologia , Animais , Peso ao Nascer/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/embriologia , Débito Cardíaco/efeitos dos fármacos , Circulação Cerebrovascular/efeitos dos fármacos , Feminino , Sangue Fetal/química , Desenvolvimento Fetal/efeitos dos fármacos , Retardo do Crescimento Fetal/fisiopatologia , Guanilato Ciclase/análise , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/enzimologia , Óxido Nítrico/fisiologia , Nitroprussiato/farmacologia , Tamanho do Órgão/efeitos dos fármacos , Placenta/irrigação sanguínea , Placenta/efeitos dos fármacos , Gravidez , Lesões Pré-Natais/fisiopatologia , Ovinos , Citrato de Sildenafila/sangue , Vasodilatação/efeitos dos fármacos
11.
Vascul Pharmacol ; 116: 16-23, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30822571

RESUMO

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


Assuntos
Proliferação de Células , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Neointima , RNA Longo não Codificante/metabolismo , Lesões do Sistema Vascular/enzimologia , Animais , Células Cultivadas , Modelos Animais de Doenças , Artéria Femoral/enzimologia , Artéria Femoral/lesões , Artéria Femoral/patologia , Hiperplasia , Masculino , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/lesões , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Fosforilação , RNA Longo não Codificante/genética , Transdução de Sinais , Lesões do Sistema Vascular/genética , Lesões do Sistema Vascular/patologia
12.
Cell Physiol Biochem ; 52(1): 76-93, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30790506

RESUMO

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


Assuntos
Membrana Celular/enzimologia , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Proteína Quinase C-alfa/metabolismo , Vasodilatação , Proteínas rho de Ligação ao GTP/metabolismo , Animais , Masculino , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , Dibutirato de 12,13-Forbol/farmacologia , Transporte Proteico/efeitos dos fármacos , Ratos , Ratos Wistar , Quinases Associadas a rho/metabolismo
13.
Ann Vasc Surg ; 57: 201-209, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30684618

RESUMO

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


Assuntos
Angioplastia com Balão/efeitos adversos , Fármacos Cardiovasculares/administração & dosagem , Lesões das Artérias Carótidas/tratamento farmacológico , Doxiciclina/administração & dosagem , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Neointima , Animais , Lesões das Artérias Carótidas/sangue , Lesões das Artérias Carótidas/enzimologia , Lesões das Artérias Carótidas/patologia , Artéria Carótida Primitiva/efeitos dos fármacos , Artéria Carótida Primitiva/enzimologia , Artéria Carótida Primitiva/patologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Hiperplasia , Metaloproteinase 14 da Matriz/sangue , Metaloproteinase 2 da Matriz/sangue , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/lesões , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Ratos Sprague-Dawley
14.
Endocrinology ; 160(1): 235-248, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30476019

RESUMO

Class II phosphoinositide 3-kinases (PI3Ks), PI3K-C2α and PI3K-C2ß, are highly homologous and distinct from class I and class III PI3Ks in catalytic products and domain structures. In contrast to class I and class III PI3Ks, physiological roles of PI3K-C2α and PI3K-C2ß are not fully understood. Because we previously demonstrated that PI3K-C2α is involved in vascular smooth muscle contraction, we studied the phenotypes of smooth muscle-specific knockout (KO) mice of PI3K-C2α and PI3K-C2ß. The pup numbers born from single PI3K-C2α-KO and single PI3K-C2ß-KO mothers were similar to those of control mothers, but those from double KO (DKO) mothers were smaller compared with control mice. However, the number of intrauterine fetuses in pregnant DKO mothers was similar to that in control mice. Both spontaneous and oxytocin-induced contraction of isolated uterine smooth muscle (USM) strips was diminished in DKO mice but not in either of the single KO mice, compared with control mice. Furthermore, contraction of USM of DKO mice was less sensitive to a Rho kinase inhibitor. Mechanistically, the extent of oxytocin-induced myosin light chain phosphorylation was greatly reduced in USM from DKO mice compared with control mice. The oxytocin-induced rise in the intracellular Ca2+ concentration in USM was similar in DKO and control mice. However, Rho activation in the intracellular compartment was substantially attenuated in DKO mice compared with control mice, as evaluated by fluorescence resonance energy transfer imaging technique. These data indicate that both PI3K-C2α and PI3K-C2ß are required for normal USM contraction and parturition mainly through their involvement in Rho activation.


Assuntos
Classe II de Fosfatidilinositol 3-Quinases/metabolismo , Músculo Liso Vascular/enzimologia , Parto , Fosfatidilinositol 3-Quinases/metabolismo , Contração Uterina , Útero/enzimologia , Proteína rhoA de Ligação ao GTP/metabolismo , Animais , Classe II de Fosfatidilinositol 3-Quinases/genética , Feminino , Camundongos , Camundongos Knockout , Contração Muscular , Músculo Liso Vascular/fisiologia , Cadeias Leves de Miosina , Fosfatidilinositol 3-Quinases/genética , Fosforilação , Útero/fisiologia , Proteína rhoA de Ligação ao GTP/genética
15.
Am J Physiol Lung Cell Mol Physiol ; 316(1): L175-L186, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30358439

RESUMO

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


Assuntos
Inibidores de Histona Desacetilases/farmacologia , Fibrose Pulmonar Idiopática/tratamento farmacológico , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Miofibroblastos/enzimologia , Proteínas Repressoras/antagonistas & inibidores , Acetilação/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Histona Desacetilases/biossíntese , Histonas/metabolismo , Humanos , Fibrose Pulmonar Idiopática/enzimologia , Fibrose Pulmonar Idiopática/patologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Miofibroblastos/patologia , PPAR gama/metabolismo , Proteínas Repressoras/biossíntese , Fator de Crescimento Transformador beta1/metabolismo
16.
Eur J Pediatr Surg ; 29(1): 102-107, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30536263

RESUMO

INTRODUCTION: Persistent pulmonary hypertension (PPH) is a major cause of morbidity and mortality in newborns with congenital diaphragmatic hernia (CDH). PPH is characterized by increased vascular resistance and smooth muscle cell (SMC) proliferation, leading to obstructive changes in the pulmonary vasculature. Nitric oxide (NO), generated by endothelial NO synthase (eNOS), is an important regulator of vascular tone and plays a key role in pulmonary vasodilatation. NO synthase interacting protein (NOSIP), which is strongly expressed by pulmonary SMCs, has recently been identified to reduce the endogenous NO production by interacting with eNOS. We designed this study to investigate the pulmonary vascular expression of NOSIP in the nitrofen-induced CDH model. MATERIALS AND METHODS: Time-mated Sprague Dawley rats received nitrofen or vehicle on gestational day 9 (D9). Fetuses were sacrificed on D21 and lung specimens divided into CDH and control (n = 6 for each group). Quantitative real-time polymerase chain reaction and Western blotting were performed to analyze pulmonary gene and protein expression of NOSIP. Immunofluorescence double staining for NOSIP was combined with a specific SMC marker to evaluate protein expression in the pulmonary vasculature. RESULTS: Relative messenger ribonucleic acid and protein expression of NOSIP was significantly decreased in nitrofen-exposed CDH lungs compared with controls. Confocal laser scanning microscopy revealed markedly diminished NOSIP immunofluorescence in nitrofen-exposed CDH lungs compared with controls, mainly in the muscular and endothelial components of the pulmonary vasculature. CONCLUSION: This study demonstrates for the first time decreased NOSIP expression in the pulmonary vasculature of the nitrofen-induced CDH. These findings suggest that NOSIP underexpression may interfere with NO production, contributing to abnormal vascular remodeling and PPH.


Assuntos
Hérnias Diafragmáticas Congênitas/enzimologia , Músculo Liso Vascular/enzimologia , Óxido Nítrico Sintase Tipo III/metabolismo , Artéria Pulmonar/enzimologia , Animais , Animais Recém-Nascidos , Proteínas de Transporte , Feminino , Expressão Gênica , Hérnias Diafragmáticas Congênitas/induzido quimicamente , Hérnias Diafragmáticas Congênitas/complicações , Pulmão/enzimologia , Masculino , Síndrome da Persistência do Padrão de Circulação Fetal/etiologia , Éteres Fenílicos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Ubiquitina-Proteína Ligases
17.
Toxicol Appl Pharmacol ; 364: 45-54, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30529164

RESUMO

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


Assuntos
Aterosclerose/prevenção & controle , Autofagia/efeitos dos fármacos , Fosfatases de Especificidade Dupla/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , RNA Longo não Codificante/metabolismo , Saponinas/farmacologia , Triterpenos/farmacologia , Calcificação Vascular/prevenção & controle , Animais , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Proteínas Relacionadas à Autofagia/metabolismo , Células Cultivadas , Modelos Animais de Doenças , Fosfatases de Especificidade Dupla/genética , Humanos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/enzimologia , Miócitos de Músculo Liso/patologia , Fosforilação , Placa Aterosclerótica , RNA Longo não Codificante/genética , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Calcificação Vascular/enzimologia , Calcificação Vascular/genética , Calcificação Vascular/patologia
18.
Cardiovasc Toxicol ; 19(3): 244-254, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30519910

RESUMO

This study investigated vildagliptin-induced vasodilation and its related mechanisms using phenylephrine induced precontracted rabbit aortic rings. Vildagliptin induced vasodilation in a concentration-dependent manner. Pretreatment with the large-conductance Ca2+-activated K+ channel blocker paxilline, ATP-sensitive K+ channel blocker glibenclamide, and inwardly rectifying K+ channel blocker Ba2+ did not affect the vasodilatory effects of vildagliptin. However, application of the voltage-dependent K+ (Kv) channel inhibitor 4-aminopyridine significantly reduced the vasodilatory effects of vildagliptin. In addition, application of either of two sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) inhibitors, thapsigargin or cyclopiazonic acid, effectively inhibited the vasodilatory effects of vildagliptin. These vasodilatory effects were not affected by pretreatment with adenylyl cyclase, protein kinase A (PKA), guanylyl cyclase, or protein kinase G (PKG) inhibitors, or by removal of the endothelium. From these results, we concluded that vildagliptin induced vasodilation via activation of Kv channels and the SERCA pump. However, other K+ channels, PKA/PKG-related signaling cascades associated with vascular dilation, and the endothelium were not involved in vildagliptin-induced vasodilation.


Assuntos
Inibidores da Dipeptidil Peptidase IV/farmacologia , Músculo Liso Vascular/efeitos dos fármacos , Canais de Potássio de Abertura Dependente da Tensão da Membrana/agonistas , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia , Vildagliptina/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/enzimologia , Ativação Enzimática , Masculino , Músculo Liso Vascular/enzimologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/metabolismo , Coelhos , Transdução de Sinais
19.
J Neuropathol Exp Neurol ; 78(2): 191-194, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30590671

RESUMO

Cerebral small vessel disease in deep penetrating arteries is a major cause of lacunar infarcts, white matter lesions and vascular cognitive impairment. Local cerebral blood flow in these small vessels is controlled by endothelial-derived nitric oxide, which exerts a primary vasodilator stimulus on vascular myocytes, via cytoplasmic cyclic GMP. Here, we investigated whether the cGMP-degrading enzyme phosphodiesterase-5 (PDE5) is present in small penetrating arteries in the deep subcortical white matter of older people. Frontal cortical tissue blocks were examined from donated brains of older people (n = 42, 24 male: 18 female, median age 81, range: 59-100 years). PDE5, detected by immunohistochemical labeling, was graded as absent, sparse, or abundant in vascular cells within small arteries in subcortical white matter (vessel outer diameter: 20-100 µm). PDE5 labeling within arterial myocytes was detected in all cases. Degree of PDE5 expression (absent, sparse, or abundant) was not associated with age or with neuropathological diagnosis of small vessel disease. In conclusion, PDE5 is present in vascular myocytes within small penetrating arteries in older people. This is a potential molecular target for pharmacological interventions.


Assuntos
Encéfalo/enzimologia , Artérias Cerebrais/enzimologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 5/metabolismo , Músculo Liso Vascular/enzimologia , Substância Branca/enzimologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Células Musculares/enzimologia
20.
Biomed Res Int ; 2018: 7902081, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30386795

RESUMO

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


Assuntos
Aspirina/uso terapêutico , Cardiotônicos/uso terapêutico , Doenças Cardiovasculares , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/prevenção & controle , Humanos
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