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1.
Life Sci ; 240: 117085, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31759042

RESUMO

AIMS: Our study was designed to explore the function and mechanism of Tanshinone IIA in alleviating pain syndrome caused by endometriosis (EMs). MAIN METHODS: Female Sprague-Dawley rats went through autotransplantation operation to establish EMs model. The rats were randomly divided into five groups: sham, model, positive, Tanshinone IIA (L) (3 mg/kg/d) and Tanshinone IIA (H) (12 mg/kg/d) group. Volume of ectopic endometrium was measured after 21 days of continuous administration. Serum estradiol (E2) was detected by enzyme linked immunosorbent assay (Elisa). The protein expression of angiotensinogen (AGT), renin (REN), angiotensin converting enzyme (ACE), angiotensin II (ANGII) and angiotensin II type 2 receptor (AT2) in the dorsal root ganglion (DRG) neurons were measured by immunohistochemistry and Western Blotting. The mRNA expression levels of AGT and ANGII were measured by Real-time polymerase chain reaction (PCR). KEY FINDINGS: Tissue measurements showed that tanshinone IIA significantly inhibited the growth of ectopic endometrium. Tanshinone IIA could improve the paw withdrawal threshold thus reducing the mechanical hyperalgesia of EMs rats. Moreover, Tanshinone IIA regulated the DRG renin angiotensin system (RAS) by reducing the protein expression of AGT, REN, ACE, ANGII and AT2 in DRG neurons. Furthermore, Real-time PCR results also showed that the mRNA expression levels of AGT and ANGII in the DRG neurons were decreased. SIGNIFICANCE: The Tanshinone IIA inhibitory effect on the EMs associated pain in EMs rats might occur through decreasing the expression of E2, ANGII and AT2, thus halting DRG sprouting and promoting hyperalgesia threshold.


Assuntos
/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Axônios/patologia , Endometriose/tratamento farmacológico , Gânglios Espinais/patologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina II/metabolismo , Animais , Endometriose/patologia , Estradiol/metabolismo , Feminino , Hiperalgesia/tratamento farmacológico , Hiperalgesia/etiologia , Ratos , Ratos Sprague-Dawley
2.
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
4.
Nan Fang Yi Ke Da Xue Xue Bao ; 39(10): 1173-1179, 2019 Oct 30.
Artigo em Chinês | MEDLINE | ID: mdl-31801713

RESUMO

OBJECTIVE: To construct a recombinant lentiviral expression vector pCDH-Daxx-EGFP to investigate the effect of Daxx on the proliferation of vascular smooth muscle cells (VSMCs). METHODS: The recombinant lentiviral expression vector pCDHDaxx-EGFP was constructed using PCR-based accurate synthesis method. After identification by sequencing and enzyme digestion, the recombinant lentiviral vector was contransfected into 293T cells with lentivirus packaging vector. The recombinant lentivirus particles were collected and purified to infect VSMCs, whose expression of Daxx was detected with Western boltting. The cells infected with the empty vector pCDH-EGFP or pCDH-Daxx-EGFP were incubated in serum-free medium or in the presence of angiotensin Ⅱ (AngⅡ). The cell viability was determined with MTT assay, and the cell cycle changes were analyzed with flow cytometry. The cell migration ability was assessed using a scratch wound healing assay. The expression of p-Akt protein in the cells was detected using Western blotting. RESULTS: Double enzyme digestion and sequencing confirmed successful construction of the recombinant plasmid. Compared with the cells infected with the empty vector, the cells infected with pCDH-Daxx-EGFP exhibited significantly increased expressions of Daxx protein (P < 0.05). AngⅡ treatment of the cells infected with the pCDH-Daxx-EGFP, as compared with the cells infected with the empty vector, significantly lowered the cell viability, S phase cell ratio and cell migration ability (P < 0.05), and significantly decreased the expression level of p-Akt protein (P < 0.05). CONCLUSIONS: We successfully constructed the recombinant lentiviral vector pCDH-Daxx-EGFP and overexpressed Daxx in primary cultured VSMCs using this vector. Daxx overexpression can inhibit AngⅡ-induced proliferation and migration in VSMCs probably by regulating p-Akt protein.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Angiotensina II/farmacologia , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Proteínas Nucleares/genética , Proliferação de Células , Vetores Genéticos , Células HEK293 , Humanos , Lentivirus , Miócitos de Músculo Liso/citologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transfecção
6.
Cell Physiol Biochem ; 53(4): 713-730, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31599538

RESUMO

BACKGROUND/AIMS: Renal injury related to hypertension is characterized by glomerular and tubulointerstitial damage. The overactivation of the renin-angiotensin system mainly by angiotensin II (AII) seems to be a main contributor to progressive renal fibrosis. Epithelial to mesenchymal transition (EMT) is a mechanism that promotes renal fibrosis. Owing to heat shock protein 70 (Hsp70) cytoprotective properties, the chaperone exhibits an important potential as a therapeutic target. We investigate the role of Hsp70 on Angiotensin II induced epithelial mesenchymal transition within the Losartan effect in proximal tubule cells (PTCs) from a genetic model of hypertension in rats (SHR). METHODS: Primary cell culture of PTCs from SHR and Wistar Kyoto (WKY) rats were stimulated with AII, treated with Losartan (L), (L+AII) or untreated (Cc). The functional Hsp70 role in Losartan effect, after silencing its expression by cell transfection, was determined by Immunofluorescence; Western blotting; Gelatin Zymography assays; Scratch wound assays; flow cytometry; and Live Cell Time-lapse microscopy. RESULTS: (L) and (L+AII) treatments induced highly organized actin filaments and increased cortical actin in SHR PTCs. However, SHR PTCs (Cc) and (AII) treated cells showed disorganized actin. After Hsp72 knockdown in SHR PTCs, (L) was unable to stabilize the actin cytoskeleton. We demonstrated that (L) and (L+AII) increased E-cadherin levels and decreased vinculin, α-SMA, vimentin, pERK, p38 and Smad2-3 activation compared to (AII) and (Cc) SHR PTCs. Moreover, (L) inhibited MMP-2 and MMP-9 secretion, reduced migration and cellular displacement, stabilizing intercellular junctions. Notably, (L) treatment in shHsp72 knockdown SHR PTCs showed results similar to SHR PTCs (Cc). CONCLUSION: Our results demonstrate that Losartan through Hsp70 inhibits the EMT induced by AII in proximal tubule cells derived from SHR.


Assuntos
Angiotensina II/farmacologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/metabolismo , Losartan/farmacologia , Citoesqueleto de Actina/efeitos dos fármacos , Animais , Caderinas/metabolismo , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Adesões Focais/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Proteínas de Choque Térmico HSP70/genética , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Vinculina/metabolismo
7.
Cell Physiol Biochem ; 53(5): 747-759, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31622062

RESUMO

BACKGROUND/AIMS: Angiotensin II (Ang II) induces podocyte injury resulting in apoptosis in vitro and in vivo. However, the relationship between autophagy and apoptosis in Ang II-induced podocyte injury is unknown and the role of Ang II-induced autophagy in podocyte survival or death remains unclear. We investigated the sequential relationship between autophagy and apoptosis in Ang II-induced podocytes as well as the role of phosphatidylinositide 3-kinase (PI3-kinase). METHODS: Mouse podocytes were incubated in media containing various concentrations of Ang II and at different incubation times. The changes of podocyte autophagy and apoptosis were observed by electron microscopy, confocal imaging, western blotting, and FACS assay according to the presence of Ang II. RESULTS: Ang II enhanced the podocyte expression of the autophagic proteins, LC3A/B-II and beclin-1, and also increased the number of autophagosomes compared with control cells at early phase of 12 hours in a dose-dependent manner. This effect was inhibited by pretreatment with 3-methyladenine (3-MA), a PI3-kinase class III inhibitor. Thereafter, the Ang II-induced enhancement in autophagy decreased, whereas, podocyte apoptosis appeared later at 24 hours in concentration- and time-dependent manners in FACS and TUNEL assays. 3-MA and LY294002, a pan PI3-kinase inhibitor, further increased Ang II-induced podocyte apoptosis. Suppression of autophagy by Atg5 siRNA could induce podocyte apoptosis and further augment high-dose Ang II-induced podocyte apoptosis. CONCLUSION: These findings suggest that Ang II promotes autophagy in podocytes before apoptosis as an early adaptive cytoprotective mechanism for podocyte survival after Ang II treatment, and the transitional imbalance between autophagy and apoptosis causes podocyte injury.


Assuntos
Angiotensina II/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Adenina/análogos & derivados , Adenina/farmacologia , Animais , Autofagossomos/metabolismo , Proteína 5 Relacionada à Autofagia/antagonistas & inibidores , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Proteína Beclina-1/metabolismo , Camundongos , Proteínas Associadas aos Microtúbulos/metabolismo , Podócitos/citologia , Podócitos/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Regulação para Cima/efeitos dos fármacos
8.
Hypertension ; 74(5): 1181-1191, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31564162

RESUMO

Brain renin angiotensin system within the paraventricular nucleus plays a critical role in balancing excitatory and inhibitory inputs to modulate sympathetic output and blood pressure regulation. We previously identified ACE2 and ADAM17 as a compensatory enzyme and a sheddase, respectively, involved in brain renin angiotensin system regulation. Here, we investigated the opposing contribution of ACE2 and ADAM17 to hypothalamic presympathetic activity and ultimately neurogenic hypertension. New mouse models were generated where ACE2 and ADAM17 were selectively knocked down from all neurons (AC-N) or Sim1 neurons (SAT), respectively. Neuronal ACE2 deletion revealed a reduction of inhibitory inputs to AC-N presympathetic neurons relevant to blood pressure regulation. Primary neuron cultures confirmed ACE2 expression on GABAergic neurons synapsing onto excitatory neurons within the hypothalamus but not on glutamatergic neurons. ADAM17 expression was shown to colocalize with angiotensin-II type 1 receptors on Sim1 neurons, and the pressor relevance of this neuronal population was demonstrated by photoactivation. Selective knockdown of ADAM17 was associated with a reduction of FosB gene expression, increased vagal tone, and prevented the acute pressor response to centrally administered angiotensin-II. Chronically, SAT mice exhibited a blunted blood pressure elevation and preserved ACE2 activity during development of salt-sensitive hypertension. Bicuculline injection in those models confirmed the supporting role of ACE2 on GABAergic tone to the paraventricular nucleus. Together, our study demonstrates the contrasting impact of ACE2 and ADAM17 on neuronal excitability of presympathetic neurons within the paraventricular nucleus and the consequences of this mutual regulation in the context of neurogenic hypertension.


Assuntos
Proteína ADAM17/metabolismo , Angiotensina II/farmacologia , Hipertensão/fisiopatologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Peptidil Dipeptidase A/metabolismo , Sistema Renina-Angiotensina/genética , Animais , Sistema Nervoso Autônomo/efeitos dos fármacos , Sistema Nervoso Autônomo/fisiopatologia , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/fisiologia , Hipertensão/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Optogenética/métodos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/patologia , Distribuição Aleatória , Sistema Renina-Angiotensina/efeitos dos fármacos
9.
BMC Infect Dis ; 19(1): 866, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31638922

RESUMO

BACKGROUND: Hand, foot and mouth disease (HFMD) remains a burdensome health issue in mainland China. Enterovirus71 (EV-A71) is the main pathogen of severe HFMD. Continuous hemofiltration improves fluid overload, restores kidney function and alleviates inflammatory reactions. The aim of the present study was to evaluate the effects of continuous veno-venous hemodiafiltration (CVVHDF) on severe HFMD caused by EV-A71(EV-A71-HFMD) in a pediatric intensive care unit (PICU). METHODS: A retrospective observational study was performed in a tertiary university PICU from January 2012 to December 2016. Children with severe EV-A71-HFMD complicated by cardiopulmonary failure were included. The patients were divided into a CVVHDF group and a conventional therapy (control) group (non-CVVHDF). The demographics, characteristics, and outcomes between the groups were collected and analyzed. RESULTS: Twenty-nine patients with severe EV-A71-HFMD were enrolled. The 28-day mortality was 17.6% (3/17) in the CVVHDF group and 33.3% (4/12) in the non-CVVHDF group, with no statistical significance between the two groups (P = 0.403). The median interval between CVVHDF initiation and PICU admission was 6 (4,8.5) hrs, and the median duration of CVVHDF was 48 (36, 64) hrs. The left ventricular ejection fraction (LVEF) and cardiac index (CI) in the CVVHDF group were improved after treatment. The plasma levels of catecholamines and renin-angiotensin-aldosterone system (RAAS) substances in the CVVHDF group were significantly decreased after treatment. The decreased catecholamines and RAAS substances included adrenalin (169.8 [145.5, 244.6] vs. 148.0 [109.0, 208.1] ng/L, P = 0.033), dopamine (152.7 [97.0, 191.1] vs. 96.0 [68.0, 160.9] ng/L, P = 0.026), angiotensin II (185.9 [125.2, 800.0] vs. 106.0 [90.8, 232.5] ng/L, P = 0.047), aldosterone (165.7 [94.0, 353.3] vs. 103.3 [84.3, 144.3] ng/L, P = 0.033), and renin (1.12 [0.74, 3.45] vs. 0.79 [0.52, 1.25] µg/L/h, P = 0.029), CONCLUSIONS: CVVHDF reduced the levels of catecholamines and RAAS substances and improved cardiovascular function. Continuous hemodiafiltration may represent a potential therapy in patients with severe EV-A71-HFMD complicated with cardiopulmonary failure.


Assuntos
Doenças Cardiovasculares/terapia , Enterovirus Humano A , Doença de Mão, Pé e Boca/terapia , Doença de Mão, Pé e Boca/virologia , Unidades de Terapia Intensiva Pediátrica , Doença Pulmonar Obstrutiva Crônica/terapia , Aldosterona/sangue , Angiotensina II/sangue , Doenças Cardiovasculares/complicações , Catecolaminas/sangue , Pré-Escolar , China , Feminino , Seguimentos , Doença de Mão, Pé e Boca/sangue , Doença de Mão, Pé e Boca/complicações , Hemodiafiltração/métodos , Humanos , Lactente , Masculino , Doença Pulmonar Obstrutiva Crônica/complicações , Renina/sangue , Sistema Renina-Angiotensina/fisiologia , Estudos Retrospectivos , Volume Sistólico , Resultado do Tratamento
10.
Life Sci ; 235: 116862, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31513814

RESUMO

Dysregulation of miR-29 has been revealed in multiple diseases, but its role in the development of hypertension and vascular endothelial dysfunction has not been defined. Here, we found that, compared with the wild-type (WT) Wistar rats, miR-29b was robustly upregulated in spontaneously hypertensive rats (SHRs), while CTRP6 was distinctly downregulated. There were two miRNA-responding-elements (MREs) for miR-29 in the 3'-UTR of CTRP6 mRNA, and the luciferase activity assay revealed that miR-29b directly targeted CTRP6 mRNA. Intraventricular injection was applied to deliver the miR-29b mimic or miR-29b inhibitor (4 mg/kg) into SHRs once two weeks from 10th week. Downregulation of miR-29b could increase serum CTRP6 content in SHRs, decrease the arterial systolic pressure, reduce serum concentrations of Ang II and ET-1, and enhance serum NO content. Meanwhile, we demonstrated that inhibition of miR-29b increased the phosphorylation of ERK1/2 to activate PPARγ, an inducer of Ang II. Finally, miR-29b expression was manipulated in, and CTRP6 recombinant protein was applied to incubate with the primary aortic endothelial cells. Inhibition of miR-29b increased CTRP6 expression, improved cell proliferation and migration, suppressed secretion of Ang II and ET-1, and decreased ROS accumulation and LDH release, displaying a similar effect to the CTRP6 recombinant protein. Moreover, the CTRP6 recombinant protein could antagonize the suppressive effect of miR-29b on activation of the ERK/PPARγ axis and function of aortic endothelial cells. In conclusion, miR-29b antagonism can alleviate Ang II-induced hypertension and vascular endothelial dysfunction through activating the CTRP6/ERK/PPARγ axis.


Assuntos
Angiotensina II/efeitos adversos , Células Endoteliais/efeitos dos fármacos , Hipertensão/genética , Hipertensão/prevenção & controle , MicroRNAs/antagonistas & inibidores , Adipocinas/sangue , Angiotensina II/sangue , Animais , Pressão Sanguínea/efeitos dos fármacos , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Regulação para Baixo/efeitos dos fármacos , Endotelina-1/sangue , Hipertensão/induzido quimicamente , Hipertensão/fisiopatologia , L-Lactato Desidrogenase/metabolismo , Masculino , MicroRNAs/agonistas , MicroRNAs/biossíntese , MicroRNAs/genética , Óxido Nítrico/sangue , Fosforilação/efeitos dos fármacos , Ratos , Ratos Endogâmicos SHR , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
12.
Int J Mol Sci ; 20(18)2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31500276

RESUMO

In various models of chronic kidney disease, the amount and localization of Cx43 in the nephron is known to increase, but the intracellular pathways that regulate these changes have not been identified. Therefore, we proposed that: "In the model of renal damage induced by infusion of angiotensin II (AngII), a RhoA/ROCK-dependent pathway, is activated and regulates the abundance of renal Cx43". In rats, we evaluated: 1) the time-point where the renal damage induced by AngII is no longer reversible; and 2) the involvement of a RhoA/ROCK-dependent pathway and its relationship with the amount of Cx43 in this irreversible stage. Systolic blood pressure (SBP) and renal function (urinary protein/urinary creatinine: Uprot/UCrea) were evaluated as systemic and organ outcomes, respectively. In kidney tissue, we also evaluated: 1) oxidative stress (amount of thiobarbituric acid reactive species), 2) inflammation (immunoperoxidase detection of the inflammatory markers ED-1 and IL-1ß), 3) fibrosis (immune detection of type III collagen; Col III) and 4) activity of RhoA/ROCK (amount of phosphorylated MYPT1; p-MYPT1). The ratio Uprot/UCrea, SBP, oxidative stress, inflammation, amount of Cx43 and p-MYPT1 remained high 2 weeks after suspending AngII treatment in rats treated for 4 weeks with AngII. These responses were not observed in rats treated with AngII for less than 4 weeks, in which all measurements returned spontaneously close to the control values after suspending AngII treatment. Rats treated with AngII for 6 weeks and co-treated for the last 4 weeks with Fasudil, an inhibitor of ROCK, showed high SBP but did not present renal damage or increased amount of renal Cx43. Therefore, renal damage induced by AngII correlates with the activation of RhoA/ROCK and the increase in Cx43 amounts and can be prevented by inhibitors of this pathway.


Assuntos
Angiotensina II/efeitos adversos , Conexina 43/metabolismo , Nefropatias/metabolismo , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/administração & dosagem , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Animais , Creatinina/urina , Modelos Animais de Doenças , Regulação da Expressão Gênica , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Nefropatias/urina , Masculino , Estresse Oxidativo , Ratos , Transdução de Sinais , Fatores de Tempo
13.
Int J Mol Sci ; 20(17)2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31480672

RESUMO

Cardiovascular diseases have a high prevalence worldwide and constitute the leading causes of mortality. Recently, malfunctioning of ß-catenin signaling has been addressed in hypertensive heart condition. Ang-II is an important mediator of cardiovascular remodeling processes which not only regulates blood pressure but also leads to pathological cardiac changes. However, the contribution of Ang-II/ß-catenin axis in hypertrophied hearts is ill-defined. Employing in vitro H9c2 cells and in vivo spontaneously hypertensive rats (SHR) cardiac tissue samples, western blot analysis, luciferase assays, nuclear-cytosolic protein extracts, and immunoprecipitation assays, we found that under hypertensive condition ß-catenin gets abnormally induced that co-activated LEF1 and lead to cardiac hypertrophy changes by up-regulating the IGF-IIR signaling pathway. We identified putative LEF1 consensus binding site on IGF-IIR promoter that could be regulated by ß-catenin/LEF1 which in turn modulate the expression of cardiac hypertrophy agents. This study suggested that suppression of ß-catenin expression under hypertensive condition could be exploited as a clinical strategy for cardiac pathological remodeling processes.


Assuntos
Cardiomegalia/induzido quimicamente , Cardiomegalia/metabolismo , Receptor IGF Tipo 2/metabolismo , Transdução de Sinais , beta Catenina/metabolismo , Angiotensina II , Animais , Biomarcadores/metabolismo , Cardiomegalia/patologia , Núcleo Celular/metabolismo , Fator de Transcrição GATA4/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Fator 1 de Ligação ao Facilitador Linfoide/metabolismo , Miócitos Cardíacos/metabolismo , Fatores de Transcrição NFATC/metabolismo , Regiões Promotoras Genéticas/genética , Proteína Quinase C-alfa/metabolismo , Ratos Endogâmicos SHR
14.
J Sci Food Agric ; 99(15): 6822-6832, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31385307

RESUMO

BACKGROUND: Angiotensin-converting enzyme (ACE) inhibitory peptides were found to alleviate acute hepatitis significantly. In this study, we purified and identified ACE inhibitory peptide from cashew to evaluate its protective role on alcohol-induced acute hepatitis in mice. RESULTS: The ACE inhibitory peptides were purified by using consecutive chromatographic techniques. One of these peptides (FETISFK) exhibited the highest ACE inhibition rate (91.04 ± 0.31%). In vivo, the results showed that ACE inhibitory peptide decreased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) caused by alcohol exposure. Moreover, it could increase the activities of superoxide dismutase (SOD) and glutathione (GSH), and decrease the level of malondialdehyde (MDA). It was also found to down-regulate markedly the expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). It could also decrease the expression of ACE, angiotensin II (AngII) and angiotensin II type 1 receptor (AT1 R). CONCLUSION: These findings support the view that the ACE inhibitory peptide alleviated acute hepatitis by down-regulating the ACE-AngII-AT1 R axis, broadening the research approach to prevent acute hepatitis, and providing experimental data for the development and utilization of cashews. © 2019 Society of Chemical Industry.


Assuntos
Anacardium/química , Inibidores da Enzima Conversora de Angiotensina/química , Hepatite/tratamento farmacológico , Peptídeos/química , Extratos Vegetais/química , Doença Aguda/terapia , Álcoois/efeitos adversos , Angiotensina II/genética , Angiotensina II/metabolismo , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Inibidores da Enzima Conversora de Angiotensina/isolamento & purificação , Animais , Aspartato Aminotransferases/genética , Aspartato Aminotransferases/metabolismo , Hepatite/enzimologia , Hepatite/etiologia , Humanos , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Camundongos , Nozes/química , Peptídeos/administração & dosagem , Peptídeos/isolamento & purificação , Peptidil Dipeptidase A/química , Peptidil Dipeptidase A/metabolismo , Extratos Vegetais/administração & dosagem , Extratos Vegetais/isolamento & purificação , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
15.
Kidney Blood Press Res ; 44(4): 792-809, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31430751

RESUMO

OBJECTIVE: We evaluated the hypothesis that the development of renal dysfunction and congestive heart failure (CHF) caused by volume overload in rats with angiotensin II (ANG II)-dependent hypertension is associated with altered renal vascular responsiveness to ANG II and to epoxyeicosatrienoic acids (EETs). METHODS: Ren-2 transgenic rats (TGRs) were used as a model of ANG II-dependent hypertension. CHF was induced by volume overload achieved by the creation of the aorto-caval fistula (ACF). Renal blood flow (RBF) responses were determined to renal arterial administration of ANG II, native 11,12-EET, an analog of 14,15-EETs (EET-A), norepinephrine (NE), acetylcholine (Ach) and bradykinin (Bk) in healthy (i.e., sham-operated) TGR and ACF TGR (5 weeks after ACF creation). RESULTS: Selective intrarenal administration of neither vasoactive drug altered mean arterial pressure in any group. Administration of ANG II caused greater decreases in RBF in ACF TGR than in sham-operated TGR, whereas after administration of NE the respective decreases were comparable in the 2 groups. Administration of Ach and Bk elicited significantly higher RBF increases in ACF TGR as compared with sham-operated TGR. In contrast, administration of 11,12-EET and EET-A caused significantly smaller RBF increases in ACF TGR than in sham-operated TGR. CONCLUSION: The findings show that 5 weeks after creation of ACF, the TGR exhibit exaggerated renal vasoconstrictor responses to ANG II and reduced renal vasodilatory responses to EETs, suggesting that both these alterations might play an important role in the development of renal dysfunction in this model of CHF.


Assuntos
Angiotensina II/efeitos adversos , Insuficiência Cardíaca/complicações , Hipertensão/induzido quimicamente , Circulação Renal/efeitos dos fármacos , Vasoconstritores/farmacologia , Animais , Fístula Artério-Arterial/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Hipertensão/complicações , Artéria Pulmonar/anormalidades , Artéria Pulmonar/fisiopatologia , Ratos , Ratos Transgênicos , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
16.
Life Sci ; 234: 116792, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31465733

RESUMO

AIMS: Assisted reproductive technologies (ART) have been widely used to treat infertility, which may impact on fetuses and offspring. This study investigated the effects of in vitro fertilization-embryo transfer (IVF-ET) on angiotensin II (AII)-mediated vasoconstrictions in umbilical cord vein, and explored possible reprogrammed methylation mechanism. MATERIALS AND METHODS: Human umbilical cords were randomly divided into ordinary pregnancy and IVF-ET pregnancy. Vascular studies with AII as well as its specific receptor antagonists losartan and PD123,319 were conducted. Real-time quantitative PCR, Western blotting, and methylation analysis by bisulfite sequencing were performed with the cord vessel samples. KEY FINDINGS: In IVF-ET group, the maximal response to AII in umbilical vessels was significantly greater than that in the ordinary pregnancy. Using losartan and PD123,319, angiotensin receptor subtype 1 (AT1R) was found mainly responsible for the enhanced contraction in the umbilical vein of IVF-ET pregnancy. Decreased mRNA expression of DNMT3A was found in umbilical vein of IVF-ET group. Hypomethylation of the AGTR1 gene (gene encoding AT1R) in the umbilical veins of the IVF group was found. The data suggested that the IVF-ET treatments altered AII-mediated vasoconstrictions in umbilical veins, which could be partially attributed to the increased expression of AT1R. SIGNIFICANCE: The hypo-methylation of the AGTR1 gene caused by IVF-ET might play important roles in altered vasoconstrictions, impacting on cardiovascular systems in the long run.


Assuntos
Angiotensina II/metabolismo , Metilação de DNA , Transferência Embrionária/métodos , Fertilização In Vitro/métodos , Receptor Tipo 1 de Angiotensina/genética , Cordão Umbilical/irrigação sanguínea , Vasoconstrição , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II/farmacologia , Anti-Hipertensivos/farmacologia , Transferência Embrionária/efeitos adversos , Feminino , Fertilização In Vitro/efeitos adversos , Humanos , Imidazóis/farmacologia , Losartan/farmacologia , Gravidez , Piridinas/farmacologia , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia
17.
Int J Mol Sci ; 20(17)2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31466304

RESUMO

Increased reactive oxygen species (ROS) induced by angiotensin II (Ang II) in the paraventricular nucleus (PVN) play a critical role in sympathetic overdrive in hypertension (OH). Intermedin (IMD), a bioactive peptide, has extensive clinically prospects in preventing and treating cardiovascular diseases. The study was designed to test the hypothesis that IMD in the PVN can inhibit the generation of ROS caused by Ang II for attenuating sympathetic nerve activity (SNA) and blood pressure (BP) in rats with obesity-related hypertension (OH). Male Sprague-Dawley rats (160-180 g) were used to induce OH by feeding of a high-fat diet (42% kcal as fat) for 12 weeks. The dynamic changes of sympathetic outflow were evaluated as the alterations of renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) responses to certain chemicals. The results showed that the protein expressions of Ang II type 1 receptor (AT1R), calcitonin receptor-like receptor (CRLR) and receptor activity-modifying protein 2 (RAMP2) and RAMP3 were markedly increased, but IMD was much lower in OH rats when compared to control rats. IMD itself microinjection into PVN not only lowered SNA, NADPH oxidase activity and ROS level, but also decreased Ang II-caused sympathetic overdrive, and increased NADPH oxidase activity, ROS levels and mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) activation in OH rats. However, those effects were mostly blocked by the adrenomedullin (AM) receptor antagonist AM22-52 pretreatment. The enhancement of SNA caused by Ang II can be significantly attenuated by the pretreatment of AT1R antagonist lorsatan, superoxide scavenger Tempol and NADPH oxidase inhibitor apocynin (Apo) in OH rats. ERK activation inhibitor U0126 in the PVN reversed Ang II-induced enhancement of SNA, and Apo and IMD pretreatment in the PVN decreased Ang II-induced ERK activation. Chronic IMD administration in the PVN resulted in significant reductions in basal SNA and BP in OH rats. Moreover, IMD lowered NADPH oxidase activity and ROS level in the PVN; reduced the protein expressions of AT1R and NADPH oxidase subunits NOX2 and NOX4, and ERK activation in the PVN; and decreased Ang II levels-inducing sympathetic overactivation. These results indicated that IMD via AM receptors in the PVN attenuates SNA and hypertension, and decreases Ang II-induced enhancement of SNA through the inhibition of NADPH oxidase activity and ERK activation.


Assuntos
Adrenomedulina/farmacologia , Anti-Hipertensivos/farmacologia , Antioxidantes/farmacologia , Hipertensão/tratamento farmacológico , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Sistema Nervoso Simpático/efeitos dos fármacos , Adrenomedulina/uso terapêutico , Angiotensina II/farmacologia , Animais , Anti-Hipertensivos/uso terapêutico , Antioxidantes/uso terapêutico , Pressão Sanguínea , Hipertensão/etiologia , Sistema de Sinalização das MAP Quinases , Masculino , NADPH Oxidases/metabolismo , Obesidade/complicações , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Hipotalâmico Paraventricular/fisiologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Sistema Nervoso Simpático/fisiopatologia
18.
Hypertension ; 74(4): 910-920, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31422690

RESUMO

Hypertension is associated with increased sympathetic activity. A component of this sympathoexcitation may be driven by increased signaling from sensory endings from the heart to the autonomic control areas in the brain. This pathway mediates the so-called cardiac sympathetic afferent reflex, which is also activated by coronary ischemia or other nociceptive stimuli in the heart. The cardiac sympathetic afferent reflex has been shown to be enhanced in the heart failure state and in renal hypertension. However, little is known about its role in the development or progression of hypertension or the phenotype of the sensory endings involved. To investigate this, we used the selective afferent neurotoxin, resiniferatoxin (RTX) to chronically abolish the cardiac sympathetic afferent reflex in 2 models of hypertension; the spontaneous hypertensive rats (SHRs) and AngII (angiotensin II) infusion (240 ng/kg per min). Blood pressure (BP) was measured in conscious animals for 2 to 8 weeks post-RTX. Epidural application of RTX to the T1-T4 spinal segments prevented the further BP increase in 8-week-old SHR and lowered BP in 16-week-old SHR. RTX did not affect BP in Wistar-Kyoto normotensive rats nor in AngII-infused rats. Epicardial application of RTX (50 µg/mL) in 4-week-old SHR prevented the BP increase whereas this treatment does not lower BP in 16-week-old SHR. When RTX was administered into the L2-L5 spinal segments of 16-week-old SHR, no change in BP was observed. These findings indicate that signaling via thoracic afferent nerve fibers may contribute to the hypertension phenotype in the SHR but not in the Ang II infusion model of hypertension.


Assuntos
Pressão Sanguínea/fisiologia , Gânglios Espinais/metabolismo , Coração/inervação , Hipertensão/metabolismo , Canais de Cátion TRPV/agonistas , Angiotensina II , Animais , Pressão Arterial/efeitos dos fármacos , Pressão Arterial/fisiologia , Pressão Sanguínea/efeitos dos fármacos , Diterpenos/farmacologia , Gânglios Espinais/efeitos dos fármacos , Coração/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Hipertensão/induzido quimicamente , Masculino , Neurotoxinas/farmacologia , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Reflexo/efeitos dos fármacos , Reflexo/fisiologia , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo
19.
Life Sci ; 233: 116745, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31404524

RESUMO

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


Assuntos
Angiotensina II/toxicidade , Endotélio Vascular/patologia , Hipertensão/patologia , Músculo Liso Vascular/patologia , PPAR gama/antagonistas & inibidores , RNA Longo não Codificante/genética , Vasoconstritores/toxicidade , Animais , Proliferação de Células , Células Cultivadas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Hipertensão/induzido quimicamente , Hipertensão/genética , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Ratos , Ratos Endogâmicos SHR , Transdução de Sinais , Remodelação Vascular
20.
Adv Exp Med Biol ; 1155: 45-59, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31468385

RESUMO

Previous studies indicate that perinatal compromise of taurine causes cardiovascular disorders in adults via the influence of taurine on renin-angiotensin system (RAS). This study tested whether perinatal inhibition of the RAS would itself alter the adult cardiovascular system in a similar way. Female Sprague-Dawley rats were fed normal rat chow and given water alone (Control) or water containing captopril (400 mg/l) from conception until weaning. Then, the male offspring drank water or water containing captopril until 5 weeks of age followed by normal rat chow and water alone until 7 weeks of age. Thereafter, they drank water alone (Control, Captopril) or 1% NaCl solution (Control+1%, Captopril+1%). At 9 weeks of age, all animals were implanted with femoral arterial and venous catheters. Forty-eight hours later, blood chemistry, glucose tolerance, and hemodynamic parameters were determined in freely moving conscious rats. Then, the same experiments were repeated 2 days after captopril treatment. Body weights, kidney and heart to body weight ratios, fasting and non-fasting blood sugar, glucose tolerance, and heart rates were not significantly different among groups. Further, plasma sodium, mean arterial pressure, and sympathetic activity significantly increased whereas baroreflex sensitivity decreased in Captopril+1% compared to other groups. These changes were normalized by acute captopril treatment and the arterial pressure differences also by acute ganglionic and central adrenergic blockade. The present study suggests that inhibition of the RAS in the early life induces RAS overactivity, leading to salt-sensitive hypertension via sympathetic nervous system overactivity and depressed baroreflex sensitivity in adult male rats.


Assuntos
Captopril/farmacologia , Hipertensão/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Angiotensina II , Animais , Barorreflexo , Pressão Sanguínea , Feminino , Masculino , Gravidez , Ratos , Ratos Sprague-Dawley , Cloreto de Sódio na Dieta
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