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1.
Int J Mol Sci ; 22(17)2021 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-34502113

RESUMO

The renin-angiotensin system (RAS) controls not only systemic functions, such as blood pressure, but also local tissue-specific events. Previous studies have shown that angiotensin II receptor type 1 (AT1R) and type 2 (AT2R), two RAS components, are expressed in chondrocytes. However, the angiotensin II (ANG II) effects exerted through these receptors on chondrocyte metabolism are not fully understood. In this study, we investigated the effects of ANG II and AT1R blockade on chondrocyte proliferation and differentiation. Firstly, we observed that ANG II significantly suppressed cell proliferation and glycosaminoglycan content in rat chondrocytic RCS cells. Additionally, ANG II decreased CCN2, which is an anabolic factor for chondrocytes, via increased MMP9. In Agtr1a-deficient RCS cells generated by the CRISPR-Cas9 system, Ccn2 and Aggrecan (Acan) expression increased. Losartan, an AT1R antagonist, blocked the ANG II-induced decrease in CCN2 production and Acan expression in RCS cells. These findings suggest that AT1R blockade reduces ANG II-induced chondrocyte degeneration. Interestingly, AT1R-positive cells, which were localized on the surface of the articular cartilage of 7-month-old mice expanded throughout the articular cartilage with aging. These findings suggest that ANG II regulates age-related cartilage degeneration through the ANG II-AT1R axis.


Assuntos
Angiotensina II/farmacologia , Condrócitos/efeitos dos fármacos , Agrecanas/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Diferenciação Celular , Linhagem Celular Tumoral , Proliferação de Células , Células Cultivadas , Condrócitos/citologia , Condrócitos/metabolismo , Condrócitos/fisiologia , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Feminino , Humanos , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 1 de Angiotensina/metabolismo
2.
Cells ; 10(7)2021 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-34359922

RESUMO

Since the end of 2019, the medical-scientific community has been facing a terrible pandemic caused by a new airborne viral agent known as SARS-CoV2. Already in the early stages of the pandemic, following the discovery that the virus uses the ACE2 cell receptor as a molecular target to infect the cells of our body, it was hypothesized that the renin-angiotensin-aldosterone system was involved in the pathogenesis of the disease. Since then, numerous studies have been published on the subject, but the exact role of the renin-angiotensin-aldosterone system in the pathogenesis of COVID-19 is still a matter of debate. RAAS represents an important protagonist in the pathogenesis of COVID-19, providing the virus with the receptor of entry into host cells and determining its organotropism. Furthermore, following infection, the virus is able to cause an increase in plasma ACE2 activity, compromising the normal function of the RAAS. This dysfunction could contribute to the establishment of the thrombo-inflammatory state characteristic of severe forms of COVID-19. Drugs targeting RAAS represent promising therapeutic options for COVID-19 sufferers.


Assuntos
COVID-19/metabolismo , Sistema Renina-Angiotensina , SARS-CoV-2/fisiologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Enzima de Conversão de Angiotensina 2/antagonistas & inibidores , Enzima de Conversão de Angiotensina 2/metabolismo , Animais , COVID-19/tratamento farmacológico , COVID-19/patologia , Descoberta de Drogas , Humanos , Terapia de Alvo Molecular , Sistema Renina-Angiotensina/efeitos dos fármacos , SARS-CoV-2/efeitos dos fármacos
3.
Int J Mol Sci ; 22(15)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34360607

RESUMO

Hypoxia and hepatosteatosis microenvironments are fundamental traits of nonalcoholic fatty liver disease (NAFLD). Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor that controls the cellular response to hypoxia and is activated in hepatocytes of patients with NAFLD, whereas the route and regulation of lipid droplets (LDs) and macrophage polarization related to systemic inflammation in NAFLD is unknown. Losartan is an angiotensin II receptor antagonist, that approved portal hypertension and related HIF-1α pathways in hepatic injury models. Here, we show that losartan in a murine model of NAFLD significantly decreased hepatic de novo lipogenesis (DNL) as well as suppressed lipid droplets (LDs), LD-associated proteins, perilipins (PLINs), and cell-death-inducing DNA-fragmentation-factor (DFF45)-like effector (CIDE) family in liver and epididymal white adipose tissues (EWAT) of ob/ob mice. Obesity-mediated macrophage M1 activation was also required for HIF-1α expression in the liver and EWAT of ob/ob mice. Administration of losartan significantly diminishes obesity-enhanced macrophage M1 activation and suppresses hepatosteatosis. Moreover, HIF-1α-mediated mitochondrial dysfunction was reversed in ob/ob mice treated with losartan. Together, the regulation of HIF-1α controls LDs protein expression and macrophage polarization, which highlights a potential target for losartan in NAFLD.


Assuntos
Fígado Gorduroso/prevenção & controle , Subunidade alfa do Fator 1 Induzível por Hipóxia/antagonistas & inibidores , Losartan/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/complicações , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Dieta Hiperlipídica , Modelos Animais de Doenças , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos
4.
J Pharm Pharm Sci ; 24: 390-399, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34319871

RESUMO

PURPOSE: SARS-CoV-2 infection is associated with substantial mortality and high morbidity. This study tested the effect of angiotensin II type I receptor blocker, losartan, on SARS-CoV-2 replication and inhibition of the papain-like protease of the virus. METHODS: The dose-dependent inhibitory effect of losartan, in concentrations from 1µM to 100µM as determined by quantitative cell analysis combining fluorescence microscopy, image processing, and cellular measurements (Cellomics analysis) on SARS-CoV-2 replication was investigated in Vero E6 cells. The impact of losartan on deubiquitination and deISGylation of SARS-CoV-2 papain-like protease (PLpro) were also evaluated.  Results: Losartan reduced PLpro cleavage of tetraUbiquitin to diUbiquitin.  It was less effective in inhibiting PLpro's cleavage of ISG15-AMC than Ubiquitin-AMC.  To determine if losartan inhibited SARS-CoV-2 replication, losartan treatment of SARS-CoV-2 infected Vero E6 was examined. Losartan treatment one hour prior to SARS-CoV-2 infection reduced levels of SARS-CoV-2 nuclear protein, an indicator of virus replication, by 80% and treatment one-hour post-infection decreased viral replication by 70%. CONCLUSION: Losartan was not an effective inhibitor of deubiquitinase or deISGylase activity of the PLpro but affected the SARS-CoV-2 replication of Vero E6 cells in vitro.  As losartan has a favorable safety profile and is currently available it has features necessary for efficacious drug repurposing and treatment of COVID-19.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Antivirais/farmacologia , Losartan/farmacologia , SARS-CoV-2/efeitos dos fármacos , Animais , COVID-19/tratamento farmacológico , Chlorocebus aethiops , Biologia Computacional , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , Enzimas Desubiquitinantes/antagonistas & inibidores , Enzimas Desubiquitinantes/metabolismo , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiologia , Ubiquitina/metabolismo , Células Vero , Replicação Viral/efeitos dos fármacos
5.
Am J Physiol Heart Circ Physiol ; 321(3): H496-H508, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34270373

RESUMO

Angiotensin II (ANG II) plays an important role in the regulation of various physiological functions including proliferation, hypertrophy of vascular smooth muscle cells (VSMCs) through the overexpression of Giα proteins. Sirtuin 1 (Sirt1), a class III histone deacetylase and epigenetic regulator is implicated in a wide range of cellular functions, including migration and growth of VSMCs and in ANG II-induced hypertension. The present study was undertaken to examine the role of Sirt1 in ANG II-induced overexpression of Giα proteins and hyperproliferation of aortic VSMCs. We show that ANG II treatment of VSMCs increased the expression of Sirt1, which was attenuated by AT1 and AT2 receptor antagonists, losartan, and PD123319, respectively. In addition, the knockdown of Sirt1 by siRNA attenuated ANG II-induced overexpression of Giα-2 and Giα-3 proteins, hyperproliferation of VSMCs and the overexpression of cell cycle proteins, cyclin D1, Cdk4, and phosphorylated retinoblastoma proteins. Furthermore, ANG II-induced increased levels of superoxide anion (O2-) and NADPH oxidase activity and increased phosphorylation of ERK1/2 and Akt that are implicated in enhanced expression of Giα proteins and hyperproliferation of VSMCs were also attenuated to control levels by silencing of Sirt1. In addition, depletion of Sirt1 by siRNA also attenuated ANG II-induced enhanced phosphorylation of platelet-derived growth factor receptor (PDGFR), epidermal growth factor receptor (EGFR), and insulin-like growth factor receptor (IGFR) in VSMCs. In summary, our results demonstrate that ANG II increased the expression of Sirt1, which through oxidative stress, growth factor receptor-mediated mitogen-activated protein (MAP) kinase/Akt signaling pathway enhances the expression of Giα proteins and cell cycle proteins and results in the hyperproliferation of VSMCs.NEW & NOTEWORTHY ANG II regulates various physiological functions including proliferation of VSMCs through the overexpression of Giα proteins. Sirt1, a class III histone deacetylase, is implicated in several cellular functions, including VSMC growth and ANG II-induced hypertension. We showed for the first time that ANG II increased the expression of Sirt1, which through oxidative stress, growth factor receptor-mediated MAP kinase/Akt signaling pathway enhances the levels of Giα and cell cycle proteins resulting in the hyperproliferation of VSMCs.


Assuntos
Angiotensina II/farmacologia , Proliferação de Células , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Sirtuína 1/genética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Aorta/citologia , Células Cultivadas , Ciclina D1/genética , Ciclina D1/metabolismo , Quinase 4 Dependente de Ciclina/genética , Quinase 4 Dependente de Ciclina/metabolismo , Receptores ErbB/genética , Receptores ErbB/metabolismo , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Humanos , Imidazóis/farmacologia , Losartan/farmacologia , Masculino , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/fisiologia , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor IGF Tipo 1/genética , Receptor IGF Tipo 1/metabolismo , Receptores do Fator de Crescimento Derivado de Plaquetas/genética , Receptores do Fator de Crescimento Derivado de Plaquetas/metabolismo , Sirtuína 1/metabolismo
6.
Int J Mol Sci ; 22(13)2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34201646

RESUMO

The physiological and pathophysiological relevance of the angiotensin II type 1 (AT1) G protein-coupled receptor no longer needs to be proven in the cardiovascular system. The renin-angiotensin system and the AT1 receptor are the targets of several classes of therapeutics (such as angiotensin converting enzyme inhibitors or angiotensin receptor blockers, ARBs) used as first-line treatments in cardiovascular diseases. The importance of AT1 in the regulation of the cerebrovascular system is also acknowledged. However, despite numerous beneficial effects in preclinical experiments, ARBs do not induce satisfactory curative results in clinical stroke studies. A better understanding of AT1 signaling and the development of biased AT1 agonists, able to selectively activate the ß-arrestin transduction pathway rather than the Gq pathway, have led to new therapeutic strategies to target detrimental effects of AT1 activation. In this paper, we review the involvement of AT1 in cerebrovascular diseases as well as recent advances in the understanding of its molecular dynamics and biased or non-biased signaling. We also describe why these alternative signaling pathways induced by ß-arrestin biased AT1 agonists could be considered as new therapeutic avenues for cerebrovascular diseases.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Receptor Tipo 1 de Angiotensina/química , Receptor Tipo 1 de Angiotensina/metabolismo , Animais , Lesões Encefálicas Traumáticas/metabolismo , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Humanos , Aneurisma Intracraniano/metabolismo , Terapia de Alvo Molecular/métodos , Transdução de Sinais/efeitos dos fármacos , Acidente Vascular Cerebral/metabolismo , beta-Arrestinas/agonistas , beta-Arrestinas/metabolismo
7.
Am J Physiol Regul Integr Comp Physiol ; 321(1): R12-R20, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34009032

RESUMO

Angiotensin II (ANG II) is a potent vasoconstrictor and may reduce renal blood flow (RBF), causing renal hypoxia. Hypotensive hemorrhage elevates plasma ANG II levels and is associated with increased risk of acute kidney injury. We hypothesized that ANG II antagonism prevents renal vasoconstriction and hypoxia caused by hemorrhage. Pigs were anaesthetized, surgically prepared, and randomized to intravenous losartan (1.5 mg·kg-1·h-1, n = 8) or an equal volume of intravenous Ringer acetate (vehicle-treated, n = 8). Hemorrhage was induced by continuous aspiration of blood to reach and sustain mean arterial pressure of <50 mmHg for 30 min. Plasma ANG II levels, hemodynamics and oxygenation were assessed 60 min prehemorrhage, 30-min after the start of hemorrhage, and 60 min posthemorrhage. Erythropoietin mRNA was analyzed in cortical and medullary tissue sampled at the end of the experiment. Hypotensive hemorrhage increased plasma ANG II levels and decreased RBF and oxygen delivery in both groups. Losartan-treated animals recovered in RBF and oxygen delivery, whereas vehicle-treated animals had persistently reduced RBF and oxygen delivery. In accordance, renal vascular resistance increased over time post hemorrhage in vehicle-treated animals but was unchanged in losartan-treated animals. Renal oxygen extraction rate and cortical erythropoietin mRNA levels increased in the vehicle group but not in the losartan group. In conclusion, ANG II antagonism alleviates prolonged renal vasoconstriction and renal hypoxia in a large animal model of hypotensive hemorrhage.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Hemorragia/patologia , Hipóxia/prevenção & controle , Rim/irrigação sanguínea , Losartan/farmacologia , Vasoconstrição/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Hemodinâmica , Hipotensão , Masculino , Oxigênio , Suínos
8.
Kidney Blood Press Res ; 46(3): 331-341, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34034251

RESUMO

BACKGROUND: Angiotensin II (Ang II) and the renal sympathetic nervous system exert a strong influence on renal sodium and water excretion. We tested the hypothesis that already low doses of an Ang II inhibitor (candesartan) will result in similar effects on tubular sodium and water reabsorption in congestive heart failure (CHF) as seen after renal denervation (DNX). METHODS: Measurement of arterial blood pressure, heart rate (HR), renal sympathetic nerve activity (RSNA), glomerular filtration rate (GFR), renal plasma flow (RPF), urine volume, and urinary sodium. To assess neural control of volume homeostasis, 21 days after the induction of CHF via myocardial infarction rats underwent volume expansion (0.9% NaCL; 10% body weight) to decrease RSNA. CHF rat and controls with or without DNX or pretreated with the Ang II type-1 receptor antagonist candesartan (0.5 ug i.v.) were studied. RESULTS: CHF rats excreted only 68 + 10.2% of the volume load (10% body weight) in 90 min. CHF rats pretreated with candesartan or after DNX excreted from 92 to 103% like controls. Decreases of RSNA induced by volume expansion were impaired in CHF rats but unaffected by candesartan pointing to an intrarenal drug effect. GFR and RPF were not significantly different in controls or CHF. CONCLUSION: The prominent function of increased RSNA - retaining salt and water - could no longer be observed after renal Ang II receptor blockade in CHF rats.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Benzimidazóis/farmacologia , Compostos de Bifenilo/farmacologia , Rim/efeitos dos fármacos , Rim/inervação , Tetrazóis/farmacologia , Angiotensina II/metabolismo , Animais , Pressão Arterial/efeitos dos fármacos , Denervação , Taxa de Filtração Glomerular/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Rim/fisiologia , Masculino , Ratos Sprague-Dawley , Sódio/metabolismo , Água/metabolismo
9.
Acta Biochim Biophys Sin (Shanghai) ; 53(6): 784-795, 2021 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-33928341

RESUMO

Autoantibody against the angiotensin II type I receptor (AT1-AA) has been found in the serum of patients with diabetes mellitus (DM). However, it remains unclear whether AT1-AA induces ß-cell apoptosis and participates in the development of DM. In this study, an AT1-AA-positive rat model was set up by active immunization, and AT1-AA IgG was purified. INS-1 cells were treated with AT1-AA, and cell viability, apoptosis, and autophagy-related proteins were detected by Cell Counting Kit-8 assay, flow cytometry, and western blot analysis, respectively. Results showed that existence of AT1-AA impaired the islet function and increased the apoptosis of pancreatic islet cells in rats, and the autophagy level in rat pancreatic islet tissues tended to increase gradually with the prolongation of immunization time. AT1-AA markedly reduced INS-1 cell viability, promoted cell apoptosis, and decreased insulin secretion in vitro. In addition, the autophagy level was gradually increased along with the prolongation of AT1-AA treatment time. Meanwhile, it was determined that treatment with autophagy inhibitor 3-methyladenine and angiotensin II type 1 receptor (AT1R) blocker telmisartan could improve insulin secretion and apoptosis in vitro and in vivo. In conclusion, it is deduced that upregulation of autophagy contributed to the AT1-AA-induced ß-cell apoptosis and islet dysfunction, and AT1R mediated the signal transduction.


Assuntos
Apoptose/efeitos dos fármacos , Autoanticorpos/imunologia , Autoanticorpos/farmacologia , Autofagia/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/farmacologia , Células Secretoras de Insulina/metabolismo , Receptor Tipo 1 de Angiotensina/imunologia , Adenina/análogos & derivados , Adenina/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Apoptose/imunologia , Autoanticorpos/isolamento & purificação , Autofagia/imunologia , Linhagem Celular Tumoral , Sobrevivência Celular/imunologia , Imunização/métodos , Imunoglobulina G/isolamento & purificação , Secreção de Insulina/efeitos dos fármacos , Secreção de Insulina/imunologia , Masculino , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologia , Telmisartan/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/imunologia
11.
Kidney Blood Press Res ; 46(2): 173-184, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33677450

RESUMO

INTRODUCTION: Angiotensin receptor blockers (ARBs) are preferably used in hypertensive patients with CKD. Azilsartan is a strong antihypertensive ARB, but its antiproteinuric effects are not well understood. We compared the antiproteinuric effect of azilsartan and candesartan in CKD patients in an open-label, randomized, crossover trial. METHODS: A total of 111 patients were treated with 20 mg of azilsartan daily for 2 months as a run-in period. After the run-in period, patients were randomized into 2 arms and received either 20 mg of azilsartan or 8 mg of candesartan daily for 3 months in a crossover trial. The primary outcome was the percent change in urinary protein-to-Cr ratio (UPCR). RESULTS: Ninety-five patients completed the trial. The mean age was 64.3 years. The estimated glomerular filtration rate (eGFR) and UPCR were 41.5 mL/min/1.73 m2 and 1.8 g/gCr, respectively. The baseline systolic and diastolic blood pressures were 131.4 and 71.0 mm Hg, respectively. The mean percent change in the UPCR was -3.8% in the azilsartan group and 30.8% in the candesartan group at the 1st endpoint (p = 0.0004), and 6.1% in the azilsartan group and 25.8% in the candesartan group at the 2nd (final) endpoint (p = 0.029). The incidence of adverse events, including eGFR levels and serum potassium levels, was not significantly different between the groups. CONCLUSION: A 20 mg azilsartan dose had potent antiproteinuric effects compared with an 8 mg candesartan dose, without an increase in adverse events. Azilsartan may provide renal protection in addition to antihypertensive effects in CKD patients.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/uso terapêutico , Compostos de Bifenilo/uso terapêutico , Oxidiazóis/uso terapêutico , Proteinúria/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Tetrazóis/uso terapêutico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Benzimidazóis/farmacologia , Compostos de Bifenilo/farmacologia , Estudos Cross-Over , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oxidiazóis/farmacologia , Tetrazóis/farmacologia
12.
Eur J Pharmacol ; 900: 174045, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33745956

RESUMO

The ubiquitin-proteasome system (UPS) plays an essential role in cellular homeostasis and myocardial function. Ubiquitin carboxy-terminal hydrolase 1 (UCHL1) is involved in cardiac remodeling, but its underlying mechanisms are largely unknown. Here, we observed that the UCHL1 was significantly up-regulated in angiotensin II-infused heart and primary cardiac fibroblast (CF). Systemic administration of the UCHL1 inhibitor LDN57444 significantly ameliorated cardiac fibrosis and improved cardiac function induced by angiotensin II. Also, LDN57444 inhibited CF cell proliferation as well as attenuated collagen I, and CTGF gene expression in the presence of Ang II. Mechanistically, UCHL1 promotes angiotensin II-induced fibrotic responses by way of activating nuclear factor kappa B (NF-κB) signaling. Moreover, suppression of the NF-κB pathway interfered with UCHL1 overexpression-mediated fibrotic responses. Besides, the chromatin immunoprecipitation assay demonstrated that NF-κB can bind to the UCHL1 promoter and trigger its transcription in cardiac fibroblasts. These findings suggest that UCHL1 positively regulates cardiac fibrosis by modulating NF-κB signaling pathway and identify UCHL1 could be a new treatment strategy for cardiac fibrosis.


Assuntos
Fibroblastos/efeitos dos fármacos , Miocárdio/patologia , NF-kappa B/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Ubiquitina Tiolesterase/antagonistas & inibidores , Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Animais Recém-Nascidos , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/antagonistas & inibidores , Colágeno Tipo I/biossíntese , Fator de Crescimento do Tecido Conjuntivo/antagonistas & inibidores , Fibrose/prevenção & controle , Camundongos , Ratos , Ratos Sprague-Dawley
13.
J Med Chem ; 64(7): 4196-4205, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33784102

RESUMO

Natural products have failed to meet the urgent need for drug discovery in recent decades due to limited resources, necessitating new strategies for re-establishing the key role of natural products in hit screening. This work introduced DNA-encoding techniques into the synthesis of phenolic acid-focused libraries containing 32 000 diverse compounds. Online selection of the library using immobilized angiotensin II type I receptor (AT1R) resulted in seven phenolic acid derivatives. The half-maximal concentration (IC50) of hit 1 for the right shift of the [125I]-Sar1-AngII competition curve was 19.6 nM. Pharmacological examination of renovascular hypertensive rats demonstrated that hit 1 significantly lowered the blood pressure of the animals without changing their heart rates. These results were used to create a general strategy for rapid and unbiased discovery of hits derived from natural products with high throughput and efficiency.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Produtos Biológicos/farmacologia , Receptor Tipo 1 de Angiotensina/metabolismo , Bloqueadores do Receptor Tipo 1 de Angiotensina II/química , Bloqueadores do Receptor Tipo 1 de Angiotensina II/metabolismo , Animais , Produtos Biológicos/química , Produtos Biológicos/metabolismo , DNA/química , Descoberta de Drogas , Ligantes , Masculino , Oligodesoxirribonucleotídeos/química , Ligação Proteica , Ratos Sprague-Dawley , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia
14.
Cardiovasc Diabetol ; 20(1): 70, 2021 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-33761942

RESUMO

BACKGROUND: The prevalence of hypertension and obesity has increased significantly in recent decades. Hypertension and obesity often coexist, and both are associated with increased cardiovascular mortality. Obese hypertensive patients usually require special anti-hypertensive treatment strategy due to the increased risk of treatment resistance. Molecules that can target both obesity and hypertension underlying pathologies should get more attention. Herein, we evaluated the therapeutic effects of telmisartan, with special interest in visceral adipose tissue dysfunction, in obesity-related hypertension rat model. METHODS: Thirty male Wistar rats weighing 150-200 g were equally divided into: 1-Control group (fed normal laboratory diet for 24 weeks), 2-Diet-induced obesity group (DIO, fed high fat diet for 24 weeks), and 3-Diet-induced obesity treated with telmisartan group (DIO + Tel, fed high fat diet and received telmisartan for 24 weeks). At the end of the study, anthropometrical parameters were evaluated. Systolic blood pressure and heart rate were measured. Blood samples were collected for the measurement of serum lipids, adipokines, cardiac, renal, inflammatory, and oxidative stress biomarkers. Kidneys were removed and used for histopathological studies, and visceral adipose tissue was utilized for histopathological, immunohistochemical and RT-PCR studies. RESULTS: High fat diet resulted in obesity-related changes in anthropometrical parameters, elevation of blood pressure, increase in heart rate, higher serum levels of cardiac, inflammatory and kidney function biomarkers, with altered serum lipids, adipokines and oxidative stress markers. Morphological changes (H&E and PAS-stained sections) were noticed in kidneys and visceral adipose tissue. Immunohistochemistry and RT-PCR studies confirmed adipose tissue dysfunction and over-expression of inflammatory and oxidative stress proteins. Telmisartan countered obesity-induced alterations in cardiovascular, renal, and adipose tissue functions. CONCLUSION: Adipose tissue dysfunction could be the core pathophysiology of obesity-related hypertension. Besides its anti-hypertensive effect, telmisartan had profound actions on visceral adipose tissue structure and function. Attention should be given to polymodal molecules targeting adipose tissue-related disorders.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Hipertensão/tratamento farmacológico , Gordura Intra-Abdominal/efeitos dos fármacos , Obesidade/complicações , Telmisartan/farmacologia , Adiposidade/efeitos dos fármacos , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Hipertensão/sangue , Hipertensão/etiologia , Hipertensão/fisiopatologia , Gordura Intra-Abdominal/metabolismo , Gordura Intra-Abdominal/fisiopatologia , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/fisiopatologia , Masculino , Obesidade/sangue , Obesidade/fisiopatologia , Ratos Wistar
15.
Am J Physiol Heart Circ Physiol ; 320(4): H1609-H1624, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33666506

RESUMO

This study aimed to determine the mechanosensing role of angiotensin II type 1 receptor (AT1R) in flow-induced dilation (FID) and oxidative stress production in middle cerebral arteries (MCA) of Sprague-Dawley rats. Eleven-week old, healthy male Sprague-Dawley rats on a standard diet were given the AT1R blocker losartan (1 mg/mL) in drinking water (losartan group) or tap water (control group) ad libitum for 7 days. Blockade of AT1R attenuated FID and acetylcholine-induced dilation was compared with control group. Nitric oxide (NO) synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) and cyclooxygenase inhibitor indomethacin (Indo) significantly reduced FID in control group. The attenuated FID in losartan group was further reduced by Indo only at Δ100 mmHg, whereas l-NAME had no effect. In losartan group, Tempol (a superoxide scavenger) restored dilatation, whereas Tempol + l-NAME together significantly reduced FID compared with restored dilatation with Tempol alone. Direct fluorescence measurements of NO and reactive oxygen species (ROS) production in MCA, in no-flow conditions revealed significantly reduced vascular NO levels with AT1R blockade compared with control group, whereas in flow condition increased the NO and ROS production in losartan group and had no effect in the control group. In losartan group, Tempol decreased ROS production in both no-flow and flow conditions. AT1R blockade elicited increased serum concentrations of ANG II, 8-iso-PGF2α, and TBARS, and decreased antioxidant enzyme activity (SOD and CAT). These results suggest that in small isolated cerebral arteries: 1) AT1 receptor maintains dilations in physiological conditions; 2) AT1R blockade leads to increased vascular and systemic oxidative stress, which underlies impaired FID.NEW & NOTEWORTHY The AT1R blockade impaired the endothelium-dependent, both flow- and acetylcholine-induced dilations of MCA by decreasing vascular NO production and increasing the level of vascular and systemic oxidative stress, whereas it mildly influenced the vascular wall inflammatory phenotype, but had no effect on the systemic inflammatory response. Our data provide functional and molecular evidence for an important role of AT1 receptor activation in physiological conditions, suggesting that AT1 receptors have multiple biological functions.


Assuntos
Circulação Cerebrovascular , Endotélio Vascular/metabolismo , Leucócitos/metabolismo , Mecanotransdução Celular , Artéria Cerebral Média/metabolismo , Estresse Oxidativo , Receptor Tipo 1 de Angiotensina/metabolismo , Vasodilatação , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Antioxidantes/farmacologia , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Circulação Cerebrovascular/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Endotélio Vascular/efeitos dos fármacos , Regulação Enzimológica da Expressão Gênica , Mediadores da Inflamação/metabolismo , Leucócitos/efeitos dos fármacos , Masculino , Mecanotransdução Celular/efeitos dos fármacos , Artéria Cerebral Média/efeitos dos fármacos , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 1 de Angiotensina/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Vasodilatadores/farmacologia
16.
J Cell Mol Med ; 25(8): 4124-4135, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33624364

RESUMO

Thrombocytopenia is independently related with increased mortality in severe septic patients. Renin-angiotensin system (RAS) is elevated in septic subjects; accumulating studies show that angiotensin II (Ang II) stimulate the intrinsic apoptosis pathway by promoting reactive oxygen species (ROS) production. However, the mechanisms underlying the relationship of platelet apoptosis and RAS system in sepsis have not been fully elucidated. The present study aimed to elucidate whether the RAS was involved in the pathogenesis of sepsis-associated thrombocytopenia and explore the underlying mechanisms. We found that elevated plasma Ang II was associated with decreased platelet count in both patients with sepsis and experimental animals exposed to lipopolysaccharide (LPS). Besides, Ang II treatment induced platelet apoptosis in a concentration-dependent manner in primary isolated platelets, which was blocked by angiotensin II type 1 receptor (AT1R) antagonist losartan, but not by angiotensin II type 2 receptor (AT2R) antagonist PD123319. Moreover, inhibiting AT1R by losartan attenuated LPS-induced platelet apoptosis and alleviated sepsis-associated thrombocytopenia. Furthermore, Ang II treatment induced oxidative stress level in a concentration-dependent manner in primary isolated platelets, which was partially reversed by the AT1R antagonist losartan. The present study demonstrated that elevated Ang II directly stimulated platelet apoptosis through promoting oxidative stress in an AT1R-dependent manner in sepsis-associated thrombocytopenia. The results would helpful for understanding the role of RAS system in sepsis-associated thrombocytopenia.


Assuntos
Angiotensina II/farmacologia , Apoptose , Plaquetas/patologia , Estresse Oxidativo , Receptor Tipo 1 de Angiotensina/metabolismo , Sepse/complicações , Trombocitopenia/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Células Cultivadas , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Prognóstico , Espécies Reativas de Oxigênio/metabolismo , Receptor Tipo 1 de Angiotensina/química , Receptor Tipo 1 de Angiotensina/genética , Transdução de Sinais , Trombocitopenia/etiologia , Trombocitopenia/metabolismo
17.
Neurourol Urodyn ; 40(1): 137-146, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33606304

RESUMO

AIMS: To investigate the effect of losartan on preventing bladder fibrosis and protecting renal function in rats with neurogenic paralysis bladder (NPB). MATERIALS AND METHODS: Rats were assigned to the transecting spinal nerves group (TSNG), transecting spinal nerves + losartan group (LSTG), and control group (CG). On Day 32 postsurgery, bladder capacity (BC), bladder compliance (ΔC), bladder leakage pressure (Pves.leak ) of TSNG and LSTG while BC, ΔC, and bladder threshold pressure (Pves.thre ) of CG were measured by cystometry in each cohort. Renal function and the expression quantity of Angiotensin Ⅱ (Ang II) in blood were detected, in addition Ang II, Ang II Type 1 receptor (AT1), transformation growth factor ß1 (TGFß1), Collagen Ⅲ, and collagen fibrin in the bladder tissue were detected too. RESULTS: ΔC in TSNG and LSTG decreased significantly compared to the CG. Pves.leak in TSNG and LSTG were significantly higher than Pves.thre in CG. Renal function of both TSNG and LSTG decreased significantly compared with the CG, but renal function in LSTG was better than in TSNG. Ang Ⅱ in blood and bladder tissue in TSNG and LSTG increased significantly compared with CG. AT1 was expressed in the bladder tissue of all rats. The TGFß1, Collagen Ⅲ, and collagen fibrin expression level increased significantly in TSNG compared with LSTG and CG, while these levels were not significantly different between CG and LSTG. CONCLUSION: Losartan might prevent NPB fibrosis by stopping the upregulated signaling of Ang II/AT1/TGFß1 and consequently may reduce kidney damage from occurring.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Fibrose/tratamento farmacológico , Losartan/uso terapêutico , Bexiga Urinaria Neurogênica/tratamento farmacológico , Bexiga Urinária/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Modelos Animais de Doenças , Losartan/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley
18.
Eur J Pharmacol ; 897: 173953, 2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33617825

RESUMO

Sepsis activates the renin-angiotensin system and the production of angiotensin II, which has a key role in the regulation of blood pressure through AT1 receptors. However, excessive activation of AT1 receptor is associated with deleterious effects. We investigated the consequences of a differential blockade of AT1 receptor caused by two doses of losartan (0.25 mg/kg or 15 mg/kg, s.c), a selective AT1 receptor antagonist on sepsis outcome. These doses reduced the effect of angiotensin II in normal rats by 30% and >90% 8 h after administration, respectively, but only the higher dose maintained its inhibitory effect (~70%) 24 h after injection. Sepsis was induced by cecal ligation and puncture (CLP). Losartan was injected 2 h after CLP and parameters were evaluated 6 and 24 h after CLP. Septic rats developed hypotension and hyporesponsiveness to vasoconstrictors, an intense inflammatory process and increase in plasma markers of organ dysfunction. The lower dose of losartan improved the vasoconstrictive response to phenylephrine and angiotensin II, reduced lung myeloperoxidase and prevented leukopenia 24 h after CLP, but it did not reduce NOS-2 expression, plasma IL-6 levels or organ injury parameters of septic rats. On the other hand, the higher dose of losartan worsened the response to vasoconstrictors, potentiated the hypotension and increased further levels of creatine, urea and lactate in septic rats. Therefore, an early and partial blockade of AT1 receptor with a low dose of losartan may counteract sepsis-induced refractoriness to vasoconstrictors thus providing an opportunity to improve the outcome of this condition.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Pressão Arterial/efeitos dos fármacos , Hipotensão/tratamento farmacológico , Losartan/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Choque Séptico/tratamento farmacológico , Vasoconstrição/efeitos dos fármacos , Vasoconstritores/farmacologia , Angiotensina II/metabolismo , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Hipotensão/metabolismo , Hipotensão/microbiologia , Hipotensão/fisiopatologia , Mediadores da Inflamação/sangue , Ratos Wistar , Receptor Tipo 2 de Angiotensina/efeitos dos fármacos , Receptor Tipo 2 de Angiotensina/metabolismo , Choque Séptico/metabolismo , Choque Séptico/microbiologia , Choque Séptico/fisiopatologia
19.
Life Sci ; 270: 119118, 2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33548284

RESUMO

Pancreatic cancer is among the most lethal malignancies with poor prognosis and patients become chemoresistant to current therapies, supporting further investigations to identify new therapeutic regimens in the treatment of this condition. Preclinical and clinical studies now appear to support the role of the renin-angiotensin system (RAS) in the regulation of tumor growth, angiogenesis, and metastasis in different malignancies including pancreatic cancer. These studies suggest that RAS blockers; Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs); could have anti-carcinogenic effects and improve clinical outcomes in the management of pancreatic cancer. Here we provided an overview of ACE inhibitors and ARBs as a potential therapeutic option in the treatment of pancreatic cancer.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Anti-Hipertensivos/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Quimioterapia Combinada , Humanos , Hipertensão/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos
20.
FASEB J ; 35(3): e21419, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33566370

RESUMO

In the early phase of the Coronavirus disease 2019 (COVID-19) pandemic, it was postulated that the renin-angiotensin-system inhibitors (RASi) increase the infection risk. This was primarily based on numerous reports, which stated that the RASi could increase the organ Angiotensin-converting enzyme 2 (ACE2), the receptor of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), in rodents. RASi can theoretically antagonize the potential influence of angiotensin II (Ang II) on ACE2. However, while Ang II decreases the ACE2 levels in cultured cells, there is little evidence that supports this phenomenon in living animals. In this study, we tested whether Ang II or Ang II combined with its antagonist would alter the ACE2 and other molecules associated with the infection of SARS-CoV-2. Male C57BL6/J mice were administered vehicle, Ang II (400 ng/kg/min), or Ang II with losartan (10 mg/kg/min) for 2 weeks. ACE2 knockout mice were used as a negative control for the ACE2 assay. We found that both Ang II, which elevated blood pressure by 30 mm Hg, and Ang II with losartan, had no effect on the expression or protein activity of ACE2 in the lung, left ventricle, kidney, and ileum. Likewise, these interventions had no effect on the expression of Transmembrane Protease Serine 2 (TMPRSS2) and Furin, proteases that facilitate the virus-cell fusion, and the expression or activity of Tumor Necrosis Factor α-Convertase (TACE) that cleaves cell-surface ACE2. Collectively, physiological concentrations of Ang II do not modulate the molecules associated with SARS-CoV-2 infection. These results support the recent observational studies suggesting that the use of RASi is not a risk factor for COVID-19.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Angiotensina II/farmacologia , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/metabolismo , Losartan/farmacologia , SARS-CoV-2 , Proteína ADAM17/genética , Proteína ADAM17/metabolismo , Angiotensina II/administração & dosagem , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Enzima de Conversão de Angiotensina 2/genética , Animais , Furina/genética , Furina/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Losartan/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Serina Endopeptidases/genética , Serina Endopeptidases/metabolismo , Vasoconstritores/farmacologia
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