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1.
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
2.
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
3.
Mar Drugs ; 17(7)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340575

RESUMO

Angiotensin II (Ang II) is closely involved in endothelial injury during the development of hypertension. In this study, the protective effects of the tilapia by-product oligopeptide Leu-Ser-Gly-Tyr-Gly-Pro (LSGYGP) on oxidative stress and endothelial injury in Angiotensin II (Ang II)-stimulated human umbilical vein endothelial cells (HUVEC) were evaluated. LSGYGP dose-dependently suppressed the fluorescence intensities of nitric oxide (NO) and reactive oxygen species (ROS), inhibited the nuclear factor-kappa B (NF-κB) pathway, and reduced inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), and endothelin-1 (ET-1) expression, as shown by western blot. In addition, it attenuated the expression of gamma-glutamyltransferase (GGT) and heme oxygenase 1 (HO-1), as well as increasing superoxide dismutase (SOD) and glutathione (GSH) expression through the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. Other experiments revealed that LSGYGP increased the apoptotic inhibition ratio between cleaved-caspase-3/procaspase-3, reduced expressions of pro-apoptotic ratio between Bcl-2/Bax, inhibited phosphorylation of mitogen-activated protein kinases (MAPK), and increased phosphorylation of the serine/threonine kinase (Akt) pathway. Furthermore, LSGYGP significantly decreased Ang II-induced DNA damage in a comet assay, and molecular docking results showed that the steady interaction between LSGYGP with NF-κB may be attributed to hydrogen bonds. These results suggest that this oligopeptide is effective in protecting against Ang II-induced HUVEC injury through the reduction of oxidative stress and alleviating endothelial damage. Thus, it has the potential for the therapeutic treatment of hypertension-associated diseases.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Hipertensão/complicações , Oligopeptídeos/farmacologia , Tilápia , Doenças Vasculares/prevenção & controle , Angiotensina II/toxicidade , Animais , Endotélio Vascular/citologia , Endotélio Vascular/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Hipertensão/patologia , Simulação de Acoplamento Molecular , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/química , NF-kappa B/metabolismo , Oligopeptídeos/química , Estresse Oxidativo/efeitos dos fármacos , Ligação Proteica , Transdução de Sinais/efeitos dos fármacos , Doenças Vasculares/patologia
4.
Hypertension ; 73(5): e14-e24, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30929511

RESUMO

Regulatory T cells (Treg cells) play important roles in hypertension and organ damages. MicroRNA-31 (miR-31) is a critical regulator for Treg cell generation. However, the role of miR-31 in hypertension has not been elucidated. We aim to study the functionality of miR-31 and the detailed mechanism in Ang II (Angiotensin II)-induced hypertensive mouse model. We found: In vitro, miR-31 expression was higher in T helper 17 cells and lower in Treg cells than that of naïve T cells. The genetic deficiency of miR-31 promoted Treg cell differentiation, whereas no impact on T helper 17 cells differentiation. Ang II-induced hypertension resulted in increased expression of miR-31 in the aorta, splenic CD4+ T cells, and kidney leukocytes. MiR-31 deficiency strikingly decreased systolic blood pressure and diastolic blood pressure and attenuated renal and vascular damage. MiR-31 deletion altered the accumulation of Treg cells and macrophages and expression of inflammatory cytokines in kidneys in Ang II-induced hypertensive mice. Ang II treatment reduced the levels of anti-inflammatory cytokines and increased proinflammatory cytokines in plasma that were blunted by the miR-31 deletion. Ppp6C (protein phosphatase 6c; a direct target of miR-31) specific deletion in Treg cells led to marked impairment of Treg cell induction, increased Ang II-induced blood pressure elevation, and organ damage in mice. In conclusion, we provided novel evidence of miR-31 as an emerging key posttranscriptional regulator of hypertension-associated immunosuppression through targeting ppp6C which is a critical regulator in the differentiation of Treg cells. This study offers new perspectives on miRNA-based therapeutic approaches.


Assuntos
Regulação da Expressão Gênica , Hipertensão/genética , Imunidade Celular/genética , MicroRNAs/genética , Fosfoproteínas Fosfatases/genética , Linfócitos T Reguladores/imunologia , Angiotensina II/toxicidade , Animais , Células Cultivadas , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Hipertensão/imunologia , Imunossupressão , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/biossíntese , Fosfoproteínas Fosfatases/biossíntese , RNA/genética , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia
5.
Hypertension ; 73(5): 1007-1017, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30929512

RESUMO

Vascular injury is an early manifestation in hypertension and a cause of end-organ damage. MicroRNAs play an important role in cardiovascular disease, but their implication in vascular injury in hypertension remains unclear. This study revealed using an unbiased approach, microRNA and mRNA sequencing with molecular interaction analysis, a microRNA-transcription factor coregulatory network involved in vascular injury in mice made hypertensive by 14-day Ang II (angiotensin II) infusion. A candidate gene approach identified upregulated miR-431-5p encoded in the conserved 12qF1 (14q32 in humans) microRNA cluster, whose expression correlated with blood pressure, and which has been shown to be upregulated in human atherosclerosis, as a potential key regulator in Ang II-induced vascular injury. Gain- and loss-of-function in human vascular smooth muscle cells demonstrated that miR-431-5p regulates in part gene expression by targeting ETS homologous factor. In vivo miR-431-5p knockdown delayed Ang II-induced blood pressure elevation and reduced vascular injury in mice, which demonstrated its potential as a target for treatment of hypertension and vascular injury.


Assuntos
Regulação da Expressão Gênica , Hipertensão/genética , MicroRNAs/genética , RNA/genética , Lesões do Sistema Vascular/genética , Angiotensina II/toxicidade , Animais , Células Cultivadas , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Hipertensão/prevenção & controle , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/biossíntese , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Lesões do Sistema Vascular/induzido quimicamente , Lesões do Sistema Vascular/prevenção & controle
6.
J Dermatol Sci ; 94(1): 205-212, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30954335

RESUMO

BACKGROUND: Systemic sclerosis (SSc) is characterized by fibrosis of the skin and internal organs. Although transforming growth factor (TGF)-ß1-induced connective tissue growth factor (CTGF/CCN2) expression has been presented in SSc fibrosis, the therapeutic potential of targeting CTGF in SSc has not been fully explored. COA-Cl is a novel nucleic acid analog, which is reported to have pleiotropic beneficial biologic effects. OBJECTIVE: We examine the effects of COA-Cl on TGF-ß1-induced CTGF expression in normal human dermal fibroblast (NHDF). We also examined the effects of COA-Cl on CTGF expression in a mouse SSc model of angiotensin II (Ang II)-induced skin fibrosis. METHODS: NHDF was cultured for in vitro experiments. For in vivo experiments, C57BL/6J mice were treated with Ang II for 14 days by subcutaneous osmotic pump. Quantitative real-time polymerase chain reaction, western blot analysis, immunohistochemical staining and immunofluorescence staining were performed to examine the expression levels of CTGF and phosphorylation levels of Smad2/3, ERK1/2 and Akt. RESULTS: COA-Cl attenuated the TGF-ß1-induced expression of both CTGF mRNA and protein in NHDF. Although COA-Cl did not alter the TGF-ß1-induced phosphorylation of Smad2/3 or ERK1/2, it reduced the TGF-ß1-induced phosphorylation levels of Akt in NHDF. Notably, COA-Cl dephosphorylated the Akt of lysates of TGF-ß1-treated NHDF. COA-Cl reduced the levels of CTGF mRNA, CTGF protein, dermal thickness, collagen content and Akt phosphorylation in the skin of mice SSc model. CONCLUSION: These results imply that the inhibition of TGF-ß1-induced CTGF expression by COA-Cl may be a therapeutic approach for SSc.


Assuntos
Adenosina/análogos & derivados , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Escleroderma Sistêmico/tratamento farmacológico , Pele/patologia , Fator de Crescimento Transformador beta1/metabolismo , Adenosina/farmacologia , Adenosina/uso terapêutico , Angiotensina II/toxicidade , Animais , Linhagem Celular , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose/tratamento farmacológico , Fibrose/etiologia , Fibrose/patologia , Humanos , Masculino , Camundongos , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Escleroderma Sistêmico/patologia , Pele/efeitos dos fármacos
7.
J Vasc Res ; 56(1): 17-27, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30879014

RESUMO

Vitamin D has an important protective effect on chronic inflammatory disease. Angiotensin II (AngII) triggers vascular damage and plays a key role in vascular diseases via several mechanisms, including inflammation. Conversely, vitamin D has been shown to have an important protective effect on chronic inflammation. There is evidence showing that vitamin D can reverse the effects of AngII, but the molecular mechanisms by which this occurs are not known. Our results demonstrate that vitamin D improved the viability, migration ability, and tube formation of AngII-pretreated endothelial progenitor cells (EPCs) and inhibited the apoptosis of EPCs induced by AngII. Vitamin D also reversed reactive oxygen species production, vascular inflammatory cytokine generation, and nuclear factor kappa-B activation in EPCs induced by AngII. Furthermore, EPC pretreatment with GW9662 (the antagonist for PPAR-γ) or siHO-1 decreased the protective effect of vitamin D on AngII-induced EPC injury. Overall, our data indicate that vitamin D ameliorated AngII-induced abnormal EPC injury by decreasing oxidative stress and inflammatory cytokine levels. These findings also suggest that vitamin D protected EPCs from AngII-induced vascular injury via the activation of the PPAR-γ/HO-1 signaling pathway.


Assuntos
Angiotensina II/toxicidade , Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Células Progenitoras Endoteliais/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , PPAR gama/metabolismo , Vitamina D/farmacologia , Apoptose/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/metabolismo , Citoproteção , Células Progenitoras Endoteliais/enzimologia , Células Progenitoras Endoteliais/patologia , Humanos , Mediadores da Inflamação/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Transdução de Sinais
8.
Hypertension ; 73(4): 829-838, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30739537

RESUMO

Hypertension is an established risk factor for subsequent cardiovascular diseases, with Ang II (angiotensin II) playing a major role in mediating thrombotic and inflammatory abnormalities. Although T cells and IL-6 (interleukin-6) play an important role in adaptive immune responses, little is known about their role(s) in the thromboinflammatory responses associated with Ang II. Here we show using intravital microscopy coupled with the light/dye injury model that Rag-1 deficient (Rag-1-/-) and IL-6 deficient (IL-6-/-) mice are afforded protection against Ang II-induced thrombosis. Blocking IL-6 receptors (using CD126 and gp130 antibodies) significantly diminished Ang II-mediated thrombosis and inflammatory cell recruitment in mice. Furthermore, the adoptive transfer of IL-6-/--derived T cells into Rag-1-/- mice failed to accelerate Ang II-induced thrombosis compared with Rag-1-/- mice reconstituted with wild-type-derived T cells, suggesting T cell IL-6 mediates the thrombotic abnormalities associated Ang II hypertension. Interestingly, adoptive transfer of WT T cells into Rag-1-/-/Ang II mice resulted in increased numbers of immature platelets, which constitutes a more active platelet population, that is, prothrombotic and proinflammatory. To translate our in vivo findings, we used clinical samples to demonstrate that IL-6 also predisposes platelets to an interaction with collagen receptors, thereby increasing the propensity for platelets to aggregate and cause thrombosis. In summary, we provide compelling evidence for the involvement of IL-6, IL-6R, and T-cell-dependent IL-6 signaling in Ang II-induced thromboinflammation, which may provide new therapeutic possibilities for drug discovery programs for the management of hypertension.


Assuntos
Imunidade Adaptativa , Pressão Sanguínea/fisiologia , Hipertensão/complicações , Hipertensão/imunologia , Interleucina-6/metabolismo , Linfócitos T/imunologia , Trombose/imunologia , Angiotensina II/toxicidade , Animais , Modelos Animais de Doenças , Citometria de Fluxo , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microcirculação/efeitos dos fármacos , Transdução de Sinais , Trombose/induzido quimicamente , Trombose/metabolismo
9.
Hypertension ; 73(4): 839-848, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30712424

RESUMO

Several experimental and clinical studies have shown that dietary nitrate supplementation can increase nitric oxide bioavailability. In the oral cavity, commensal bacteria reduce nitrate to nitrite, which is subsequently absorbed into the circulation where reduction to nitric oxide by enzymatic systems occur. Although it is well-known that boosting the nitrate-nitrite-nitric oxide pathway can improve cardiovascular, renal, and metabolic functions and that sympathoexcitation contributes to the development of the same disorders, the potential effects of dietary nitrate on sympathetic activity remain to be elucidated. In this study, we hypothesized that treatment with inorganic nitrate could prevent the increase in sympathetic nerve activity in an experimental model of Ang II (angiotensin II)-induced hypertension. Multiple in vivo approaches were combined, that is, Wistar rats orally treated with the nitric oxide synthase inhibitor L-NAME (N(G)-nitro-L-arginine methyl ester, 0.5 g/L) and implanted with subcutaneous osmotic minipump for continuous delivery of Ang II (120 ng/kg per minute; 14 days). Simultaneously, rats were supplemented with sodium nitrate (10 mmol/L) or placebo (sodium chloride; 10 mmol/L) in the drinking water. Blood pressure, heart rate, and renal sympathetic nerve activity were recorded. In placebo-treated rats, Ang II+L-NAME treatment-induced arterial hypertension, which was linked with reduced spontaneous baroreflex sensitivity and increased renal sympathetic nerve activity, as well as upregulation of AT1Rs (Ang II type-1 receptors) in the rostral ventrolateral medulla. Supplementation with nitrate normalized the expression of AT1Rs in rostral ventrolateral medulla and reduced sympathetic nerve activity, which was associated with attenuated development of hypertension. In conclusion, chronic dietary nitrate supplementation blunted the development of hypertension via mechanisms that involve reduction of sympathetic outflow.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Hipertensão/terapia , Nitratos/farmacologia , Sistema Nervoso Simpático/fisiopatologia , Angiotensina II/toxicidade , Animais , Barorreflexo/efeitos dos fármacos , Suplementos Nutricionais , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Masculino , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar
10.
Basic Res Cardiol ; 114(2): 8, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30643968

RESUMO

Mice with a global deletion of α1AMPK are characterized by endothelial dysfunction and NADPH oxidase subunit 2 (NOX-2)-mediated vascular oxidative stress. However, the underlying mechanisms are incompletely understood and may involve endothelial NOX-2 upregulation or facilitated vascular infiltration of phagocytic cells. Therefore, the current study was designed to investigate the vascular effects of chronic angiotensin II (AngII) infusion in mice with an endothelial-specific α1AMPK deletion. A mouse strain with endothelial-specific α1AMPK deletion was generated by breeding α1AMPKflox/flox mice with TekCre+ or Cadh5Cre+ mice. Chronic AngII infusion (0.5 mg/kg/day for 7day) caused mild endothelial dysfunction in wild-type mice that was significantly aggravated in endothelial α1AMPK knockout mice. Aortic NOX-2 and CD68 expression were increased, indicating that infiltrating leukocytes may significantly contribute to enhanced vascular oxidative stress. Flow cytometry revealed a higher abundance of aortic CD90.2+ T-cells, CD11b+F4/80+ macrophages and Ly6G-Ly6C+ monocytes. Vascular mRNA expression of monocyte chemoattractant protein 1, CCL5 and vascular cell adhesion molecule 1 was enhanced in AngII-infused mice lacking endothelial α1AMPK, facilitating the recruitment of inflammatory cells to the vessel wall. In addition, AngII-induced upregulation of cytoprotective heme oxygenase 1 (HO-1) was blunted in mice with endothelial α1AMPK deletion, compatible with an impaired antioxidant defense in these animals. In summary, endothelial expressed α1AMPK limits the recruitment of inflammatory cells to the vessel wall and maintains HO-1 mediated antioxidant defense. Both mechanisms reduce vascular oxidative damage and preserve endothelial function during chronic AngII treatment.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Endotélio Vascular/metabolismo , Angiotensina II/toxicidade , Animais , Antioxidantes/metabolismo , Endotélio Vascular/efeitos dos fármacos , Heme Oxigenase-1/metabolismo , Inflamação/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia
11.
Hypertension ; 73(3): 547-560, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30686087

RESUMO

p53-dependent vascular smooth muscle cell senescence is a key pathological process of abdominal aortic aneurysm (AAA). Caloric restriction (CR) is a nonpharmacological intervention that prevents AAA formation. However, whether p53 is indispensable to the protective role of CR remains unknown. In this study, we investigated the necessity of p53 in the beneficial role of CR in AAA formation and the underlying mechanisms. We subjected p53+/+ and p53-/- mice to 12 weeks of CR and then examined the incidence of Ang II (angiotensin II)-induced AAA formation. We found that both CR and p53 knockout reduced Ang II-induced AAA formation; however, CR markedly increased the incidence of AAA formation and exacerbated aortic elastin degradation in p53-/- mice, accompanied by increased vascular senescence, reactive oxygen species generation, and reduced energy production. Analysis of mitochondrial respiratory activity revealed that dysfunctional complex IV accounts for the abnormal mitochondrial respiration in p53-/- vascular smooth muscle cells treated by CR serum. Mechanistically, ablation of p53 almost totally blocked the protective role of CR by inhibiting SCO2 (cytochrome C oxidase assembly protein 2)-dependent mitochondrial complex IV activity. Overexpression of SCO2 restored the beneficial effect of CR on antagonizing Ang II-induced expression of AAA-related molecules and reactive oxygen species generation in p53-/- vascular smooth muscle cells. Together, our findings demonstrate that the existence of p53 in vascular smooth muscle cells is critical to the protective role of CR in Ang II-induced AAA formation by maintaining an appropriate mitochondrial function.


Assuntos
Aneurisma da Aorta Abdominal/terapia , Restrição Calórica/métodos , Metabolismo Energético/fisiologia , Músculo Liso Vascular/metabolismo , Proteína Supressora de Tumor p53/genética , Angiotensina II/toxicidade , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Proteína Supressora de Tumor p53/metabolismo
12.
Biol Pharm Bull ; 42(1): 18-25, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30606987

RESUMO

Hypertension is a disease of high prevalence and morbidity where vascular inflammation and associated oxidative stress (endothelial dysfunction) is the underlying cause of this pathology. We are reporting the antihypertensive activity of extracts and fractions of Malva parviflora in mice with chronic and acute hypertension. Also, the treatments of this plant were able to counteract the kidney inflammation and associated oxidative stress. The chronic hypertension model consisted of administration of angiotensin II (AGII) during 12 weeks, causing a sustained increase in systolic (SBP) or diastolic (DBP) pressure, with values of pharmacological constants of: ED50 = 0.038 mg/kg y Emax = 135 mmHg for SBP and ED50 = 0.046 mg/kg y Emax = 98 mmHg for DBP. The chronic hypertension caused the inflammation and lipid peroxidation in kidneys, measured by of tissue level of cytokines such as interleukin-1ß (IL-1ß), IL-6, Tumor Necrosis Factor-α (TNF-α), IL-10 and malondialdehyde, and treatments for M. parviflora were able to modulate these parameters. The chemical fractionation allowed to identify three compounds: oleanolic acid, tiliroside and scopoletin, which were tested in a model of acute hypertension. The pharmacodynamic parameters for SBP were ED50 = 0.01 and 0.12 mg/kg while Emax = 33.22 and 37.74 mmHg for scopoletin and tiliroside, respectively; whereas that for DBP data were ED50 = 0.01 and 0.02 mg/kg; with an Emax = 7.00 and 6.24 mmHg, in the same order. M. parviflora, is able to counteract the effect of chronic and acute administration of AGII, on hypertension, but also the inflammatory and oxidative damage in the kidney. The oleanolic acid, scopoletin and tiliroside are the compounds responsible for such activities.


Assuntos
Anti-Hipertensivos/uso terapêutico , Flavonoides/uso terapêutico , Hipertensão/tratamento farmacológico , Malva , Extratos Vegetais/uso terapêutico , Escopoletina/uso terapêutico , Angiotensina II/toxicidade , Animais , Anti-Hipertensivos/isolamento & purificação , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Relação Dose-Resposta a Droga , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Hipertensão/sangue , Hipertensão/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos ICR , Extratos Vegetais/isolamento & purificação , Escopoletina/isolamento & purificação , Escopoletina/farmacologia
13.
FASEB J ; 33(1): 494-500, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30118322

RESUMO

Dimethylarginine dimethylaminohydrolases (DDAHs) are known to degrade asymmetric dimethylarginine, an endogenous inhibitor of NOS, and maintain vascular homeostasis; however, the regulatory pathways of DDAHs remain unclear. In this study, we aimed to define the role of transmembrane glycoprotein neuropilin-1 (NRP1) in the expression of DDAHs and investigate the potential roles of NRP1 in regulation of blood pressure. Short hairpin RNA-mediated knockdown of NRP1 reduced the level and mRNA stability of DDAH1 but not DDAH2 in HUVECs, whereas overexpression of NRP1 increased the mRNA stability of DDAH1. Meanwhile, mesenteric arteries and lung vascular endothelial cells of tamoxifen-inducible endothelial cell-specific NRP1 knockout mice exhibited decreased expression of DDAH1 and slightly increased expression of DDAH2. Mechanistically, the regulation of NRP1 on DDAH1 expression is mediated by a posttranscriptional mechanism involving miR-219-5p in HUVECs. Although the endothelial cell-specific NRP1 knockout mice did not exhibit any significant change in blood pressure at the basal level, they were more sensitive to low-dose angiotensin II infusion-induced increases in blood pressure. Our results show that NRP1 is required for full expression of DDAH1 in endothelial cells and that NRP1 contributes to protection from low-dose angiotensin II-induced increases in blood pressure.-Wang, Y., Wang, E., Zhang, Y., Madamsetty, V. S., Ji, B., Radisky, D. C., Grande, J. P., Misra, S., Mukhopadhyay, D. Neuropilin-1 maintains dimethylarginine dimethylaminohydrolase 1 expression in endothelial cells, and contributes to protection from angiotensin II-induced hypertension.


Assuntos
Amidoidrolases/fisiologia , Angiotensina II/toxicidade , Endotélio Vascular/efeitos dos fármacos , Hipertensão/prevenção & controle , Neuropilina-1/fisiologia , Vasoconstritores/toxicidade , Animais , Arginina/análogos & derivados , Arginina/metabolismo , Pressão Sanguínea , Células Cultivadas , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Hipertensão/induzido quimicamente , Hipertensão/metabolismo , Masculino , Camundongos , Camundongos Knockout , Óxido Nítrico/metabolismo
14.
Biomed Pharmacother ; 110: 155-167, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30469080

RESUMO

Amphioctopus neglectus (Family: Octopodidae) is recognised as culinary delicacy in many cultures and a common sea food item on the Mediterranean and Asian coasts. Bioassay-directed fractionation of ethyl acetate/methanol extract of A. neglectus ensued in the characterisation of four previously undescribed macrocyclic lactones (1-4). These compounds exhibited potential radical-scavenging capacities (IC50 0.95-1.73 mM) along with anti-hypertensive activities (IC50 1.12-2.34 mM) against angiotensin converting enzyme (ACE). The optimum binding affinity of compound 2 (-9.84 kcal mol-1) bearing furo[1,4,8]trioxacyclohexadecine-12,19-dione moiety with ACE, along with its permissible hydrophobic-hydrophilic balance, manifested towards its greater anti-hypertensive activity compared to other analogues. The compound 2, with lesser values of the inhibitory constant (Ki = 1.0 mM) towards ACE, was found to bind more effectively to the enzyme in a non-competitive manner, and could describe the greater inhibitory ramifications than those displayed by other compounds (Ki >1.1 mM). The ex-vivo studies revealed that compound 2 imparted protective effects against angiotensin-II induced cardiac hypertrophy at 25 µg mL-1 on H9C2 cell lines, wherein about 34 percent decrease in cell area with increase in viability could be attributed to anti-hypertrophic effects of the compound administrated. These results confirmed that the protective effect of the isolated macrocyclic lactones is mediated by enhancement of anti-oxidant defense systems, which subsequently attenuates the hypertensive related disorders.


Assuntos
Angiotensina II/toxicidade , Produtos Biológicos/uso terapêutico , Cardiomegalia/induzido quimicamente , Cardiomegalia/prevenção & controle , Lactonas/uso terapêutico , Simulação de Acoplamento Molecular/métodos , Animais , Antioxidantes/química , Antioxidantes/isolamento & purificação , Antioxidantes/uso terapêutico , Produtos Biológicos/química , Produtos Biológicos/isolamento & purificação , Cardiomegalia/metabolismo , Linhagem Celular , Lactonas/química , Lactonas/isolamento & purificação , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Octopodiformes , Relação Estrutura-Atividade
15.
Biomed Pharmacother ; 109: 1287-1295, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30463808

RESUMO

Aortic stenosis (AS) is considered to be an actively regulated progress that involves similar pathophysiological processes as atherosclerosis. I-κB kinase-ε (IKKε) is a proinflammatory molecule involved in atherosclerosis. The objective of the present study was to define the role of IKKε in pathological valvular remodeling. Aortic valves (AVs) from 52 patients undergoing AV replacement (AS) and 13 patients undergoing heart transplant (Control) were analyzed. ApoE-/- mice (AK, n = 20) and ApoE-/-IKKε-/- mice (DK, n = 20) were generated and infused with saline or Ang II for 4 weeks. We found an upregulation of IKKε in human stenotic aortic valves compared to that in control AVs. Our results demonstrated that AK mice receiving AngII exhibited more advanced valvular remodeling and markedly increased IKKε expression. Conversely, loss of IKKε reduced adverse aortic valve thickening in response to Ang II, as measured by histological analyses. Furthermore, according to immunofluorescence analysis, Ang II resulted in obvious increases in the expression of α-SMA, TGF-ß and NF-κB pathway components in the AK group, especially in the thickened area, while these increases were blocked in the DK group. Moreover, IKKε was co-expressed with α-SMA in valvular interstitial cells in ApoE-/- mice after an AngII infusion. These data provide evidence that IKKε plays a key role in the development of valvular remodeling and that it may be a novel target for the treatment of AS.


Assuntos
Angiotensina II/toxicidade , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/prevenção & controle , Valva Aórtica/metabolismo , Apolipoproteínas E/deficiência , Quinase I-kappa B/deficiência , Adulto , Idoso , Animais , Valva Aórtica/efeitos dos fármacos , Estenose da Valva Aórtica/patologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade
16.
FEBS J ; 286(1): 46-65, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30548183

RESUMO

Previous studies have demonstrated that activation of calcineurin induces pathological cardiac hypertrophy (CH). In these studies, loss-of-function was mostly achieved by systemic administration of the calcineurin inhibitor cyclosporin A. The lack of conditional knockout models for calcineurin function has impeded progress toward defining the role of this protein during the onset and the development of CH in adults. Here, we exploited a mouse model of CH based on the infusion of a hypertensive dose of angiotensin II (AngII) to model the role of calcineurin in CH in adulthood. AngII-induced CH in adult mice was reduced by treatment with cyclosporin A, without affecting the associated increase in blood pressure, and also by induction of calcineurin deletion in adult mouse cardiomyocytes, indicating that cardiomyocyte calcineurin is required for AngII-induced CH. Surprisingly, cardiac-specific deletion of calcineurin, but not treatment of mice with cyclosporin A, significantly reduced AngII-induced cardiac fibrosis and apoptosis. Analysis of profibrotic genes revealed that AngII-induced expression of Tgfß family members and Lox was not inhibited by cyclosporin A but was markedly reduced by cardiac-specific calcineurin deletion. These results show that AngII induces a direct, calcineurin-dependent prohypertrophic effect in cardiomyocytes, as well as a systemic hypertensive effect that is independent of calcineurin activity.


Assuntos
Calcineurina/fisiologia , Cardiomegalia/patologia , Fibrose/patologia , Miócitos Cardíacos/patologia , Angiotensina II/toxicidade , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Progressão da Doença , Fibrose/induzido quimicamente , Fibrose/metabolismo , Perfilação da Expressão Gênica , Camundongos , Camundongos Knockout , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Transdução de Sinais , Vasoconstritores/toxicidade
17.
Am J Physiol Renal Physiol ; 316(2): F396-F407, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30539655

RESUMO

Accumulating evidence demonstrates that mitochondrial dysfunction and inflammasome activation play a critical role in the pathogenesis of renal tubular injury through the production of reactive oxygen species and cytokines. Prohibitin 2 (PHB2) is a newly identified intracellular receptor of mitophagy (a type of autophagy) that mediates selective removal of damaged mitochondria, and it could possibly play a renoprotective role in kidney disease. In this study, we confirmed that autophagy is activated in tubular epithelial cells treated with angiotensin II and that inhibition of autophagy results in tubular cell injury. Strikingly, PHB2 knockdown reduced the level of mitophagy and augmented cell death, while overexpression of PHB2 provided protection against pyrin domain-containing protein 3 (NLRP3)-induced inflammatory pathways through amelioration of mitochondrial dysfunction. Our research is the first to experimentally demonstrate the role of PHB2 in renal proximal tubular cells and thereby to provide a better understanding of how autophagy modulates inflammation in renal tubules. These data highlight PHB2 as a therapeutic target in the future treatment of CKD.


Assuntos
Apoptose , Células Epiteliais/metabolismo , Inflamassomos/metabolismo , Túbulos Renais Proximais/metabolismo , Mitocôndrias/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteínas Repressoras/metabolismo , Angiotensina II/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Humanos , Inflamassomos/efeitos dos fármacos , Túbulos Renais Proximais/efeitos dos fármacos , Túbulos Renais Proximais/patologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Proteínas Repressoras/genética , Transdução de Sinais
18.
J Am Heart Assoc ; 8(1): e010418, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30563389

RESUMO

Background Cardiac fibrosis is a core pathological process associated with heart failure. The recruitment and differentiation of primitive fibroblast precursor cells of bone marrow origin play a critical role in pathological interstitial cardiac fibrosis. The KC a3.1 channels are expressed in both ventricular fibroblasts and circulating mononuclear cells in rats and are upregulated by angiotensin II . We hypothesized that KC a3.1 channels mediate the inflammatory microenvironment in the heart, promoting the infiltrated bone marrow-derived circulating mononuclear cells to differentiate into myofibroblasts, leading to myocardial fibrosis. Methods and Results We established a cardiac fibrosis model in rats by infusing angiotensin II to evaluate the impact of the specific KC a3.1 channel blocker TRAM -34 on cardiac fibrosis. At the same time, mouse CD 4+ T cells and rat circulating mononuclear cells were separated to investigate the underlying mechanism of the TRAM -34 anti-cardiac fibrosis effect. TRAM -34 significantly attenuated cardiac fibrosis and the inflammatory reaction and reduced the number of fibroblast precursor cells and myofibroblasts. Inhibition of KC a3.1 channels suppressed angiotensin II -stimulated expression and secretion of interleukin-4 and interleukin-13 in CD 4+ T cells and interleukin-4- or interleukin-13-induced differentiation of monocytes into fibrocytes. Conclusions KC a3.1 channels facilitate myocardial inflammation and the differentiation of bone marrow-derived monocytes into myofibroblasts in cardiac fibrosis caused by angiotensin II infusion.


Assuntos
Cardiomiopatias/genética , Regulação da Expressão Gênica , Inflamação/genética , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/genética , Monócitos/patologia , Miocárdio/metabolismo , Angiotensina II/toxicidade , Animais , Western Blotting , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Imuno-Histoquímica , Inflamação/metabolismo , Inflamação/patologia , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/biossíntese , Masculino , Monócitos/metabolismo , Miocárdio/patologia , Miofibroblastos/metabolismo , Miofibroblastos/patologia , RNA/genética , Ratos , Ratos Sprague-Dawley
19.
J Am Heart Assoc ; 8(1): e009372, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30572753

RESUMO

Background Immune cells are key regulators of the vascular inflammatory response characteristic of hypertension. In hypertensive rodents, regulatory T lymphocytes (Treg, CD 4+ CD 25+) prevented vascular injury, cardiac damage, and endothelial dysfunction of mesenteric arteries. Whether Treg modulate the cerebrovascular damage induced by hypertension is unknown. Methods and Results C57 BL /6 mice were perfused with angiotensin II (Ang II ; 1000 ng/kg per minute) for 14 days and adoptive transfer of 3×105 CD 4+ CD 25+ T cells was performed via 2 intravenous injections. Control mice received a sham surgery and PBS . Treg prevented Ang II -induced neurovascular uncoupling ( P<0.05) and endothelial impairment ( P<0.05), evaluated by laser Doppler flowmetry in the somatosensory cortex. The neuroprotective effect of Treg was abolished when they were isolated from mice deficient in interleukin-10. Administration of interleukin-10 (60 ng/d) to hypertensive mice prevented Ang II -induced neurovascular uncoupling ( P<0.05). Treg adoptive transfer also diminished systemic inflammation induced by Ang II ( P<0.05), examined with a peripheral blood cytokine array. Mice receiving Ang II + Treg exhibited reduced numbers of Iba-1+ cells in the brain cortex ( P<0.05) and hippocampus ( P<0.001) compared with mice infused only with Ang II. Treg prevented the increase in cerebral superoxide radicals. Overall, these effects did not appear to be directly modulated by Treg accumulating in the brain parenchyma, because only a nonsignificant number of Treg were detected in brain. Instead, Treg penetrated peripheral tissues such as the kidney, inguinal lymph nodes, and the spleen. Conclusions Treg prevent impaired cerebrovascular responses in Ang II -induced hypertension. The neuroprotective effects of Treg involve the modulation of inflammation in the brain and periphery.


Assuntos
Pressão Sanguínea/fisiologia , Circulação Cerebrovascular/fisiologia , Hipertensão/imunologia , Imunidade Inata , Linfócitos T Reguladores/imunologia , Angiotensina II/toxicidade , Animais , Modelos Animais de Doenças , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , Fluxometria por Laser-Doppler , Masculino , Camundongos , Camundongos Endogâmicos C57BL
20.
Exp Neurol ; 311: 173-181, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30315807

RESUMO

Autonomic dysreflexia (AD), a syndrome caused by loss of supraspinal control over sympathetic activity and amplified vascular reflex upon sensory stimuli below injury level, is a major health problem in high-level spinal cord injury (SCI). After supraspinal sympathetic control of the vasculature below the lesion is lost, the renin-angiotensin system (RAS) is thought to be involved in AD by regulating blood pressure and vascular reactivity. In this study, we aimed to assess the role of different RAS receptors during AD following SCI. Therefore, we induced AD by colorectal distention (CRD) in wild-type mice and mice deficient in the RAS components angiotensin (Ang) II type 1a receptor (AT1a) (Agtr1a-/-) and Ang-(1-7) receptor Mas (Mas-/-) four weeks after complete transection of spinal cord at thoracic level 4 (T4). Systemic blood pressure measurements and wire myography technique were performed to assess hemodynamics and the reactivity of peripheral arteries, respectively. CRD increased mean arterial blood pressure (MAP) and decreased heart rate (HR) in all three animal groups. However, we found less increases in MAP in Mas-/- mice compared to control mice after CRD, whereas AT1a deficiency did not affect the hemodynamic response. We found that the reactivity of wild-type and Mas-/- mesenteric arteries, which are innervated from ganglia distal but close to thoracic level T4, was diminished in response to Ang II in AD after T4-SCI, but this difference was not observed in the absence of AT1a receptors. CRD did not influence the reactivity of femoral arteries which are innervated from ganglia more distal to thoracic level T4, in response to Ang II in AD. In conclusion, we identified a specific role of the Ang-(1-7) receptor Mas in regulating the systemic blood pressure increase in AD in T4-SCI mice. Furthermore, AT1a signaling is not involved in this hemodynamic response, but underlies increased vascular reactivity in mesenteric arteries in response to Ang II, where it may contribute to adaptive changes in regional blood flow.


Assuntos
Disreflexia Autonômica/metabolismo , Disreflexia Autonômica/fisiopatologia , Receptores de Angiotensina/fisiologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/fisiopatologia , Angiotensina II/toxicidade , Animais , Disreflexia Autonômica/etiologia , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Traumatismos da Medula Espinal/complicações , Vértebras Torácicas
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