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1.
Hum Genet ; 139(4): 447-459, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32076828

RESUMO

Low-density lipoprotein receptor-related protein 6 (LRP6) is a member of the low-density lipoprotein receptors (LDLRs) family and accumulating evidence points to the critical role of LRP6 in cardiovascular health and homeostasis. In addition to presenting the well-appreciated roles in canonical signaling regulating blood pressure, blood glucose, lipid metabolism, atherosclerosis, cardiac valve disease, cardiac development, Alzheimer's disease and tumorigenesis, LRP6 also inhibits non-canonical Wnt signals that promote arterial smooth muscle cell proliferation and vascular calcification. Noticeably, the role of LRP6 is displayed in cardiometabolic disease, an increasingly important clinical burden with aging and obesity. The prospect for cardiovascular diseases treatment via targeting LRP6-mediated signaling pathways may improve central blood pressure and lipid metabolism, and reduce neointima formation and myocardial ischemia-reperfusion injury. Thus, a deep and comprehensive understanding of LRP6 structure, function and signaling pathways will contribute to clinical diagnosis, therapy and new drug development for LRP6-related cardiovascular diseases.


Assuntos
Doenças Cardiovasculares , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Transdução de Sinais , Calcificação Vascular , Via de Sinalização Wnt , Envelhecimento/metabolismo , Envelhecimento/patologia , Animais , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/terapia , Humanos , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química , Proteína-6 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Obesidade/metabolismo , Obesidade/patologia , Relação Estrutura-Atividade , Calcificação Vascular/diagnóstico , Calcificação Vascular/metabolismo , Calcificação Vascular/patologia , Calcificação Vascular/terapia
2.
Life Sci ; 248: 117445, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32081664

RESUMO

AIMS: Atherosclerosis (AS) is a common cardiovascular disease with complicated pathogenesis. Long non-coding RNAs (lncRNAs) have been reported to be associated with AS progression. We aimed to explore the role and underlying mechanism of HOXA transcript at the distal tip (HOTTIP) in AS. MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to detect the expression of HOTTIP, miR-490-3p and high mobility group B 1 (HMGB1) in AS patients' sera and oxidized low-density lipoprotein (ox-LDL) induced human aortic vascular smooth muscle cells (HA-VSMCs). Cell Counting Kit-8 (CCK-8) assay and transwell assay were conducted to evaluate the proliferation and migration of HA-VSMCs, respectively. Western blot assay was carried out to determine the levels of proliferating cell nuclear antigen (PCNA), matrix metalloprotein 2 (MMP2), MMP9 and HMGB1. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were conducted to verify the targeting association between HOTTIP and miR-490-3p, as well as miR-490-3p and HMGB1. KEY FINDINGS: HOTTIP and HMGB1 were upregulated and miR-490-3p was downregulated in the sera of AS patients and ox-LDL-stimulated HA-VSMCs. HOTTIP knockdown suppressed ox-LDL induced proliferation and migration in HA-VSMCs. MiR-490-3p was identified as a target of HOTTIP and HOTTIP overexpression abolished the inhibition on cell proliferation and migration mediated by miR-490-3p in ox-LDL-induced HA-VSMCs. Moreover, miR-490-3p inhibition promoted cell proliferation and migration by directly targeting HMGB1 in ox-LDL-induced HA-VSMCs. Besides, HOTTIP knockdown repressed the activation of PI3K-AKT signaling pathway. SIGNIFICANCE: HOTTIP knockdown suppressed cell proliferation and migration by regulating miR-490-3p/HMGB1 axis and PI3K-AKT pathway in ox-LDL-induced HA-VSMCs.


Assuntos
Aterosclerose/genética , Proteína HMGB1/genética , MicroRNAs/genética , Miócitos de Músculo Liso/metabolismo , Fosfatidilinositol 3-Quinases/genética , Proteínas Proto-Oncogênicas c-akt/genética , RNA Longo não Codificante/genética , Aorta/metabolismo , Aorta/patologia , Aterosclerose/sangue , Aterosclerose/patologia , Estudos de Casos e Controles , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica , Proteína HMGB1/metabolismo , Humanos , Lipoproteínas LDL/farmacologia , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Antígeno Nuclear de Célula em Proliferação/genética , Antígeno Nuclear de Célula em Proliferação/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução de Sinais
3.
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
4.
Cell Prolif ; 53(1): e12711, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31737960

RESUMO

OBJECTIVES: Vascular disorders are associated with phenotypical switching of vascular smooth muscle cells (VSMCs). We investigated the effect of bone morphogenetic protein (BMP)-2 in controlling VSMC phenotype and vascular disorder progression. Lysine (K)-specific demethylase 1A (KDM1A) has been identified to target BMP-2 and is employed as a therapeutic means of regulating BMP-2 expression in VSMCs. MATERIALS AND METHODS: VSMCs were stimulated with angiotensin II, and the expression of KDM1A and BMP-2 was detected. VSMC proliferation, apoptosis, and phenotype were evaluated. An in vivo aortic injury model was established, and VSMC behaviour was evaluated by the expression of key markers. The activation of BMP-2-associated signalling pathways was examined. RESULTS: We confirmed the inhibitory effect of KDM1A on BMP-2 activity and demonstrated that KDM1A inhibition prevented VSMC transformation from a contractile to synthetic phenotype. In angiotensin II-treated VSMCs, KDM1A inhibition triggered a decrease in cell proliferation and inflammatory response. In vivo, KDM1A inhibition alleviated post-surgery neointimal formation and collagen deposition, preventing VSMCs from switching into a synthetic phenotype and suppressing disease onset. These processes were mediated by BMP-2 through canonical small mothers against decapentaplegic signalling, which was associated with the activation of BMP receptors 1A and 1B. CONCLUSIONS: The regulatory correlation between KDM1A and BMP-2 offers insights into vascular remodelling and VSMC phenotypic modulation. The reported findings contribute to the development of innovative strategies against vascular disorders.


Assuntos
Proteína Morfogenética Óssea 2/metabolismo , Histona Desmetilases , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Neointima/metabolismo , Remodelação Vascular , Animais , Células Cultivadas , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases/metabolismo , Hiperplasia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Neointima/patologia , Ratos , Ratos Sprague-Dawley
5.
Life Sci ; 241: 117144, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31830482

RESUMO

BACKGROUND: As an inflammation-related cytokine, interleukin (IL)-5 has been reported to be involved in the development of cardiovascular diseases, such as chronic heart failure and atherosclerosis. However, the role of IL-5 in acute aortic dissection (AAD) has barely been explored. METHODS: Aortic tissue samples from normal donors and patients with AAD were collected, and the expression and localization of IL-5 in aortic tissue were analyzed. In addition, a mouse AAD model was established by administering angiotensin II (Ang II) to ß-aminopropionitrile (BAPN)-treated mice. Morphological examinations and histopathologic analyses were performed to evaluate the effects of IL-5 overexpression on the occurrence of AAD. RESULTS: IL-5 expression was significantly decreased in aorta samples from AAD patients compared to those from donors, and macrophages were the main source of IL-5. In addition, IL-5 expression was decreased in plasma and aortic tissue samples from AAD mice. IL-5 overexpression markedly attenuated the occurrence of AAD in mice and produced corresponding decreases in the inflammatory response and cell apoptosis. In cocultures of macrophages and smooth muscle cells (SMCs), IL-5 overexpression in the macrophages significantly reduced Ang II-induced SMC apoptosis. CONCLUSION: IL-5 overexpression suppresses the development of AAD by reducing inflammation and SMC apoptosis. These results suggest that IL-5 is a potential therapeutic target in AAD.


Assuntos
Aneurisma Dissecante/prevenção & controle , Apoptose , Modelos Animais de Doenças , Inflamação/prevenção & controle , Interleucina-5/metabolismo , Macrófagos/patologia , Miócitos de Músculo Liso/patologia , Aminopropionitrilo/toxicidade , Aneurisma Dissecante/induzido quimicamente , Aneurisma Dissecante/complicações , Aneurisma Dissecante/metabolismo , Angiotensina II/toxicidade , Animais , Aorta/metabolismo , Aorta/patologia , Estudos de Casos e Controles , Feminino , Humanos , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Interleucina-5/genética , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Miócitos de Músculo Liso/metabolismo , Prognóstico
6.
Adv Exp Med Biol ; 1131: 471-487, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31646521

RESUMO

All seven canonical transient potential receptor (TRPC1-7) channel members are expressed in mammalian airway smooth muscle cells (ASMCs). Among this family, TRPC3 channel plays an important role in the control of the resting [Ca2+]i and agonist-induced increase in [Ca2+]i. This channel is significantly upregulated in molecular expression and functional activity in airway diseases. The upregulated channel significantly augments the resting [Ca2+]i and agonist-induced increase in [Ca2+]i, thereby exerting a direct and essential effect in airway hyperresponsiveness. The increased TRPC3 channel-mediated Ca2+ signaling also results in the transcription factor nuclear factor-κB (NF-κB) activation via protein kinase C-α (PKCα)-dependent inhibitor of NFκB-α (IκBα) and calcineurin-dependent IκBß signaling pathways, which upregulates cyclin-D1 expression and causes cell proliferation, leading to airway remodeling. TRPC3 channel may further interact with intracellular release Ca2+ channels, Orai channels and Ca2+-sensing stromal interaction molecules, mediating important cellular responses in ASMCs and the development of airway diseases.


Assuntos
Cálcio , Miócitos de Músculo Liso , Canais de Cátion TRPC , Animais , Calcineurina/metabolismo , Cálcio/metabolismo , Proliferação de Células/genética , Humanos , Miócitos de Músculo Liso/patologia , Miócitos de Músculo Liso/fisiologia , Sistema Respiratório/fisiopatologia , Canais de Cátion TRPC/metabolismo
7.
Biol Res ; 52(1): 59, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801629

RESUMO

OBJECTIVES: In varicose veins, vascular smooth muscle cells (VSMCs) often shows phenotypic transition and abnormal proliferation and migration. Evidence suggests the FOXC2-Notch pathway may be involved in the pathogenesis of varicose veins. Here, this study aimed to explore the role of long non-coding RNA FOXC2-AS1 (FOXC2 antisense RNA 1) in phenotypic transition, proliferation, and migration of varicose vein-derived VSMCs and to explore whether the FOXC2-Notch pathway was involved in this process. METHODS: The effect of FOXC2-AS1 on the proliferation and migration of human great saphenous vein smooth muscle cells (SV-SMCs) was analyzed using MTT assay and Transwell migration assay, respectively. The levels of contractile marker SM22α and synthetic marker osteopontin were measured by immunohistochemistry and Western blot to assess the phenotypic transition. RESULTS: The human varicose veins showed thickened intima, media and adventitia layers, increased synthetic VSMCs, as well as upregulated FOXC2-AS1 and FOXC2 expression. In vitro assays showed that FOXC2-AS1 overexpression promoted phenotypic transition, proliferation, and migration of SV-SMCs. However, the effect of FOXC2-AS1 overexpression could be abrogated by both FOXC2 silencing and the Notch signaling inhibitor FLI-06. Furthermore, FOXC2-AS1 overexpression activated the Notch pathway by upregulating FOXC2. CONCLUSION: FOXC2-AS1 overexpression promotes phenotypic transition, proliferation, and migration of SV-SMCs, at least partially, by activating the FOXC2-Notch pathway.


Assuntos
Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Fatores de Transcrição Forkhead/metabolismo , Miócitos de Músculo Liso/metabolismo , Veia Safena/metabolismo , Células Cultivadas , Humanos , Miócitos de Músculo Liso/patologia , Fenótipo , Veia Safena/patologia , Transdução de Sinais , Regulação para Cima
8.
Life Sci ; 237: 116896, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31605707

RESUMO

AIMS: Population-based studies have shown that exercise has anti-atherosclerotic effects, but the mechanisms underlying this cardiac protection are poorly understood. The aim of this study was to investigate if the anti-atherosclerotic effects of exercise are associated with changes in neuropeptide Y (NPY) expression in apolipoprotein E-deficient (ApoE-/-) mice. MAIN METHODS: Thirty-one male ApoE-/- mice were randomly divided into regular exercise (5 days/week), occasional exercise (1-2 days/week), and sedentary groups. After 8 weeks, atherosclerotic burden and plaque stability were measured by histological and morphological analysis. Quantitative real-time PCR and immunohistochemistry were used to measure the expression of NPY and its receptors in the aorta. KEY FINDINGS: Eight weeks of occasional exercise was equally effective as regular exercise at preventing atherosclerotic plaque formation and enhancing atherosclerotic plaque stability. This was shown by increased plaque collagen and smooth muscle cell content and decreased plaque lipid and macrophage content. The expression of NPY and its receptors in the vasculature was decreased in the regular exercise and occasional exercise groups, and this expression was significantly correlated with the progress of atherosclerosis. Moreover, exercise may reduce the activity of macrophages by down-regulating the expression of NPY Y1 receptors, thereby reducing the release of inflammatory cytokines. SIGNIFICANCE: These results suggest that exercise training can attenuate plaque burden and enhance atherosclerotic plaque stability. The anti-atherosclerotic effect of exercise appears to be, at least in part, dependent on down-regulation of the expression of NPY and its receptors (especially Y1 receptors) in the aorta.


Assuntos
Apolipoproteínas E/fisiologia , Aterosclerose/prevenção & controle , Regulação da Expressão Gênica , Inflamação/prevenção & controle , Neuropeptídeo Y/metabolismo , Condicionamento Físico Animal , Animais , Aorta/metabolismo , Aorta/patologia , Aterosclerose/etiologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Neuropeptídeo Y/genética
9.
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
10.
Nat Commun ; 10(1): 3551, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31391533

RESUMO

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease of cardiopulmonary units. No cure is currently available due to an incomplete understanding of vascular remodeling. Here we identify CD146-hypoxia-inducible transcription factor 1 alpha (HIF-1α) cross-regulation as a key determinant in vascular remodeling and PAH pathogenesis. CD146 is markedly upregulated in pulmonary artery smooth muscle cells (PASMCs/SMCs) and in proportion to disease severity. CD146 expression and HIF-1α transcriptional program reinforce each other to physiologically enable PASMCs to adopt a more synthetic phenotype. Disruption of CD146-HIF-1α cross-talk by genetic ablation of Cd146 in SMCs mitigates pulmonary vascular remodeling in chronic hypoxic mice. Strikingly, targeting of this axis with anti-CD146 antibodies alleviates established pulmonary hypertension (PH) and enhances cardiac function in two rodent models. This study provides mechanistic insights into hypoxic reprogramming that permits vascular remodeling, and thus provides proof of concept for anti-remodeling therapy for PAH through direct modulation of CD146-HIF-1α cross-regulation.


Assuntos
Retroalimentação Fisiológica , Hipertensão Pulmonar/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Remodelação Vascular , Animais , Antígeno CD146/genética , Antígeno CD146/metabolismo , Hipóxia Celular , Células Cultivadas , Modelos Animais de Doenças , Humanos , Hipertensão Pulmonar/diagnóstico , Hipertensão Pulmonar/etiologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Masculino , Camundongos , Camundongos Knockout , Monocrotalina/toxicidade , Músculo Liso Vascular/citologia , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Cultura Primária de Células , Artéria Pulmonar/citologia , Artéria Pulmonar/patologia , Ratos , Índice de Gravidade de Doença , Regulação para Cima
11.
Int J Mol Sci ; 20(15)2019 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-31370156

RESUMO

Diabetes mellitus is one of the major risk factors for cardiovascular disease and is an important health issue worldwide. Long-term diabetes causes endothelial dysfunction, which in turn leads to diabetic vascular complications. Endothelium-derived nitric oxide is a major vasodilator in large-size vessels, and the hyperpolarization of vascular smooth muscle cells mediated by the endothelium plays a central role in agonist-mediated and flow-mediated vasodilation in resistance-size vessels. Although the mechanisms underlying diabetic vascular complications are multifactorial and complex, impairment of endothelium-dependent hyperpolarization (EDH) of vascular smooth muscle cells would contribute at least partly to the initiation and progression of microvascular complications of diabetes. In this review, we present the current knowledge about the pathophysiology and underlying mechanisms of impaired EDH in diabetes in animals and humans. We also discuss potential therapeutic approaches aimed at the prevention and restoration of EDH in diabetes.


Assuntos
Fatores Biológicos/genética , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Endotélio Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Canais de Potássio Cálcio-Ativados/genética , Animais , Fatores Biológicos/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/genética , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/patologia , Junções Comunicantes/efeitos dos fármacos , Junções Comunicantes/metabolismo , Junções Comunicantes/patologia , Regulação da Expressão Gênica , Humanos , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Potenciais da Membrana/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Canais de Potássio Cálcio-Ativados/metabolismo , Fatores de Risco , Transdução de Sinais , Vasodilatação/efeitos dos fármacos
12.
Biomed Pharmacother ; 117: 108986, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387172

RESUMO

Chemokine-like factor 1 (CKLF1) is a cytokine, which has a detrimental effect on the multiple disease progression. Our previous studies reported that arterial injury induced the upregulation of CKLF1 expression in artery at 7-14 days after injury. Here, using a rat carotid balloon injury model, we found that CKLF1 knockdown in the injured site abolished neointimal formation and even decreased medial area; contrarily, CKLF1 overexpression developed a thicker neointima than controls, demonstrating that CKLF1 exerted positive effects on neointimal hyperplasia and the accumulation of vascular smooth muscle cells (VSMC). The mechanism study indicated that CKLF1 reduced susceptibility to the cell cycle G2/M arrest and apoptosis, and thereby speeding up VSMC accumulation. This role of CKLF1 was tightly associated with phosphatidylinositol (PI) 3-kinase signaling pathway. CKLF1 increased the expression of four isoforms of the PI3-kinase catalytic subunits, which in turn activated its downstream targets Akt and an effector NF-κB accepted as critical transcription factors of cell survival and proliferation. Furthermore, RNA-sequencing analysis revealed that CKLF1 had wide-ranging roles in regulating the expression of genes that mainly engaged in cell apoptosis and innate immune response. Collectively, the data allow us to conclude that high level CKLF1 after artery injury switches the balance of VSMC proliferation and apoptosis through PI3K/AKT/NF-κB signaling and consequently leads to neointimal hyperplasia. The findings shed insight into new treatment strategies to limit restenosis based on CKLF1 as a future target.


Assuntos
Apoptose/fisiologia , Quimiocinas/metabolismo , Hiperplasia/metabolismo , Proteínas com Domínio MARVEL/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Neointima/metabolismo , Transdução de Sinais/fisiologia , Animais , Divisão Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Pontos de Checagem da Fase G2 do Ciclo Celular/fisiologia , Hiperplasia/patologia , Masculino , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , NF-kappa B/metabolismo , Neointima/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley
13.
J Vasc Res ; 56(6): 308-319, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31437850

RESUMO

Tumor necrosis factor (TNF) receptor-associated factors (TRAFs) are cytoplasmic adaptor proteins of the TNF/interleukin (IL)-1/Toll-like receptor superfamily. Ligands of this family such as TNFα, CD40L, and IL-1ß promote chronic inflammatory processes such as atherosclerosis and restenosis, the latter being a common adverse reaction after vascular interventions. We previously reported overexpression of TRAF5 in murine and human atheromata and TRAF5-dependent proinflammatory functions in vitro. However, the role of TRAF5 in restenosis remains unsettled. To evaluate whether TRAF5 affects neointima formation, TRAF5-/-LDLR-/- and TRAF5+/+LDLR-/- mice consuming a high cholesterol diet (HCD) received wire-induced injury of the carotid artery. After 28 days, TRAF5-deficient mice showed a 45% decrease in neointimal area formation compared with TRAF5-compentent mice. Furthermore, neointimal vascular smooth muscle cells (vSMC) and macrophages decreased whereas collagen increased in TRAF5-deficient mice. Mechanistically, the latter expressed lower transcript levels of the matrix metalloproteinases 2 and 9, both instrumental in extracellular matrix degradation and vSMC mobilization. Additionally, TRAF5-specific siRNA interference rendered murine vSMC less proliferative upon CD40L stimulation. In accordance with these findings, fewer vSMC isolated from TRAF5-deficient aortas were in a proliferative state as assessed by Ki67 and cyclin B1 expression. In conclusion, TRAF5 deficiency mitigates neointima formation in mice, likely through a TRAF5-dependent decrease in vSMC proliferation.


Assuntos
Doenças das Artérias Carótidas/metabolismo , Proliferação de Células , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Neointima , Fator 5 Associado a Receptor de TNF/metabolismo , Animais , Antígenos CD40/metabolismo , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/genética , Doenças das Artérias Carótidas/patologia , Colesterol na Dieta , Modelos Animais de Doenças , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Placa Aterosclerótica , Receptores de LDL/genética , Receptores de LDL/metabolismo , Transdução de Sinais , Fator 5 Associado a Receptor de TNF/deficiência , Fator 5 Associado a Receptor de TNF/genética
14.
Microsc Res Tech ; 82(12): 2000-2006, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31448474

RESUMO

Vascular calcification (VC) is highly prevalent in patients with chronic kidney disease (CKD) and contributes to their high rate of cardiovascular mortality. Indoxyl sulfate (IS) is a representative protein-bound uremic toxin in CKD patients, which has been recognized as a major risk factor for VC. Recent studies have demonstrated that nuclear factor-kappa B (NK-κB) is highly activated in the chronic inflammation conditions of CKD patients and participated in the pathogenesis of VC. However, whether NK-κB is involved in the progression of IS-induced VC remains without elucidation. Here, we showed that NK-κB activity was increased in the IS-induced calcification of human aortic smooth muscle cells (HASMCs). Blocking the NK-κB with a selective inhibitor (Bay-11-7082) significantly relieved the osteogenic transdifferentiation of HASMCs, characterized by the downregulation of early osteogenic-specific marker, core-binding factor alpha subunit 1 (Cbfα1), and upregulation of smooth muscle α-actin (α-SMA), a specific vascular smooth muscle cell marker. Besides, IS stimulated the activation of PI3K/Akt signaling. Furthermore, LY294002, a specific inhibitor of PI3K/Akt pathway, attenuated the activation of NK-κB and osteogenic differentiation of HASMCs. Together, these results suggest that PI3K/Akt/NK-κB signaling plays an important role in the pathogenesis of osteogenic transdifferentiation induced by IS.


Assuntos
Indicã/toxicidade , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , NF-kappa B/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Calcificação Vascular/patologia , Actinas/biossíntese , Linhagem Celular , Cromonas/farmacologia , Subunidade alfa 1 de Fator de Ligação ao Core/biossíntese , Regulação para Baixo/efeitos dos fármacos , Humanos , Morfolinas/farmacologia , NF-kappa B/antagonistas & inibidores , Nitrilos/farmacologia , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Insuficiência Renal Crônica/patologia , Transdução de Sinais , Sulfonas/farmacologia , Regulação para Cima/efeitos dos fármacos
15.
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
16.
Biochimie ; 165: 1-8, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31255603

RESUMO

Cardiovascular diseases (CVDs) are the first cause of death in the World. Mediator (MED) is an evolutionarily conserved protein complex, which mediates distinct protein-protein interactions. Pathogenic events in MED subunit have been associated with human diseases. Novel increasing evidence showed that missense mutations in MED13L gene are associated with transposition of great arteries while MED12, MED13, MED15, and MED30, have been correlated with heart development. Moreover, MED23 and MED25 have been associated with heart malformations in humans. Relevantly, MED1, MED13, MED14, MED15, MED23, MED25, and CDK8, were found modify glucose and/or lipid metabolism. Indeed, MED1, MED15, MED25, and CDK8 interact in the PPAR- and SREBP-mediated signaling pathways. MED1, MED14 and MED23 are involved in adipocyte differentiation, whereas MED23 mediates smooth muscle cell differentiation. MED12, MED19, MED23, and MED30 regulate endothelial differentiation by alternative splicing mechanism. Thus, MEDs have a central role in early pathogenic events involved in CVDs representing novel targets for clinical prevention and therapeutic approaches.


Assuntos
Cardiopatias Congênitas , Complexo Mediador , Adipogenia , Processamento Alternativo , Animais , Glucose/metabolismo , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/metabolismo , Cardiopatias Congênitas/patologia , Humanos , Metabolismo dos Lipídeos , Complexo Mediador/genética , Complexo Mediador/fisiologia , Camundongos , Miocárdio/patologia , Miócitos de Músculo Liso/patologia
18.
Biomed Res Int ; 2019: 9174218, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31346526

RESUMO

Background: Intermittent hypoxia (IH) induced by obstructive sleep apnea (OSA) is a leading factor affecting cardiovascular fibrosis. Under IH condition, smooth muscle cells (SMAs) respond by dedifferentiation, which is associated with vascular remodelling. The expression of prolyl 4-hydroxylase domain protein 3 (PHD3) increases under hypoxia. However, the role of PHD3 in OSA-induced SMA dedifferentiation and cardiovascular fibrosis remains uncertain. Methods: We explored the mechanism of cardiovascular remodelling in C57BL/6 mice exposed to IH for 3 months and investigated the mechanism of PHD3 in improving the remodelling in vivo and vitro. Results: In vivo remodelling showed that IH induced cardiovascular fibrosis via SMC dedifferentiation and that fibrosis improved when PHD3 was overexpressed. In vitro remodelling showed that IH induced SMA dedifferentiation, which secretes much collagen I. PHD3 overexpression in cultured SMCs reversed the dedifferentiation by degrading and inactivating HIF-1α. Conclusion: OSA-induced cardiovascular fibrosis was associated with SMC dedifferentiation, and PHD3 overexpression may benefit its prevention by reversing the dedifferentiation. Therefore, PHD3 overexpression has therapeutic potential in disease treatment.


Assuntos
Cardiomiopatias/genética , Fibrose/genética , Pró-Colágeno-Prolina Dioxigenase/genética , Apneia Obstrutiva do Sono/genética , Animais , Cardiomiopatias/etiologia , Cardiomiopatias/patologia , Desdiferenciação Celular/genética , Hipóxia Celular/genética , Modelos Animais de Doenças , Fibrose/etiologia , Fibrose/patologia , Regulação da Expressão Gênica/genética , Humanos , Camundongos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/patologia
19.
Biomed Res Int ; 2019: 7159592, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31355277

RESUMO

Cardiac remodeling is a self-regulatory response of the myocardium and vasculature under the stressful condition. Cardiomyocytes (CMs), vascular smooth muscle cells (VSMCs), endothelial cells (ECs), and cardiac fibroblasts (CFs) are all involved in this process, characterized by change of morphological structures and mechanical/chemical activities as well as metabolic patterns. Despite current development of consciousness, the control of cardiac remodeling remains unsatisfactory, and to further explore the underlying mechanism and seek the optimal therapeutic targets is still the urgent need in clinical practice. It is now emerging that long noncoding RNAs (lncRNAs) play key regulatory roles in these adverse responses: lncRNA TUG1, AK098656, TRPV1, GAS5, Giver, and Lnc-Ang362 have been indicated in hypertension-related vascular remodeling, H19, TUG1, UCA1, MEG3, APPAT, and lincRNA-p21 in atherosclerosis (AS), and HIF1A-AS1 and Lnc-HLTF-5 in aortic aneurysm (AA). In addition, Neat1, AK139328, APF, CAIF, AK088388, CARL, MALAT1, HOTAIR, XIST, and NRF are involved in postischemia myocardial remodeling, while Mhrt, Chast, CHRF, ROR, H19, Plscr4, and MIAT are involved in myocardial hypertrophy, and MALAT1, wisper, MEG3, and H19 are involved in extracellular matrix (ECM) reconstitution. Signaling to specific miRNAs by acting as endogenous sponge (ceRNA) was the main form that regulates the target gene expression during cardiac remodeling. This review will underline the updates of lncRNAs and lncRNA-miRNA interactions in maladaptive remodeling and also cast light on their potential roles as therapeutic targets, hoping to provide supportive background for following research.


Assuntos
Matriz Extracelular/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Remodelação Ventricular , Animais , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Matriz Extracelular/patologia , Humanos , Miocárdio/patologia , Miócitos Cardíacos/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia
20.
Acta Pharmacol Sin ; 40(10): 1322-1333, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31316183

RESUMO

Abnormal wound healing by pulmonary artery smooth muscle cells (PASMCs) promotes vascular remodeling in hypoxia-induced pulmonary hypertension (HPH). Increasing evidence shows that both the mammalian target of rapamycin complex 1 (mTORC1) and nuclear factor-kappa B (NF-κB) are involved in the development of HPH. In this study, we explored the crosstalk between mTORC1 and NF-κB in PASMCs cultured under hypoxic condition and in a rat model of hypoxia-induced pulmonary hypertension (HPH). We showed that hypoxia promoted wound healing of PASMCs, which was dose-dependently blocked by the mTORC1 inhibitor rapamycin (5-20 nM). In PASMCs, hypoxia activated mTORC1, which in turn promoted the phosphorylation of NF-κB. Molecular docking revealed that mTOR interacted with IκB kinases (IKKs) and that was validated by immunoprecipitation. In vitro kinase assays and mass spectrometry demonstrated that mTOR phosphorylated IKKα and IKKß separately. Inhibition of mTORC1 decreased the level of phosphorylated IKKα/ß, thus reducing the phosphorylation and transcriptional activity of NF-κB. Bioinformatics study revealed that dipeptidyl peptidase-4 (DPP4) was a target gene of NF-κB; DPP4 inhibitor, sitagliptin (10-500 µM) effectively inhibited the abnormal wound healing of PASMCs under hypoxic condition. In the rat model of HPH, we showed that NF-κB activation (at 3 weeks) was preceded by mTOR signaling activation (after 1 or 2 weeks) in lungs, and administration of sitagliptin (1-5 mg/kg every day, ig) produced preventive effects against the development of HPH. In conclusion, hypoxia activates the crosstalk between mTORC1 and NF-κB, and increased DPP4 expression in PASMCs that leads to vascular remodeling. Sitagliptin, a DPP4 inhibitor, exerts preventive effect against HPH.


Assuntos
Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Artéria Pulmonar/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Administração Oral , Animais , Hipóxia Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Biologia Computacional , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/administração & dosagem , Inibidores da Dipeptidil Peptidase IV/farmacologia , Modelos Animais de Doenças , Células HEK293 , Humanos , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , NF-kappa B/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Fosfato de Sitagliptina/administração & dosagem , Fosfato de Sitagliptina/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Cicatrização/efeitos dos fármacos
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