RESUMO
INTRODUCTION: Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that produces a broad spectrum of clinical conditions such as dementia, upper motor neuron involvement, extrapyramidal symptoms, and neuropathy. Some studies have reported ophthalmological conditions associated with the disease; however, the details of these conditions remain unclear. PATIENT CONCERNS: We report a 63-year-old Japanese female with cognitive decline, blurred vision, photophobia, and color blindness at 52 years of age who was diagnosed with cone dystrophy. She also had anxiety, insomnia, depression, delusions, hallucinations, a wide-based gait with short steps, and urinary incontinence. DIAGNOSES, INTERVENTIONS, AND OUTCOMES: Magnetic resonance imaging revealed diffuse cerebral white matter changes and subcortical hyperintensity on diffusion-weighted imaging. Skin biopsy showed p62-positive intranuclear inclusions in sweat glands. NOTCH2NLC gene analysis revealed abnormal GGC expansion; therefore, NIID was diagnosed. CONCLUSION: NOTCH2NLC mutation-positive NIID may be associated with retinal dystrophy. Brain magnetic resonance imaging and skin biopsy are helpful diagnostic clues, and gene analysis is crucial for accurate diagnosis and appropriate management.
Assuntos
Doenças Neurodegenerativas , Distrofias Retinianas , Humanos , Feminino , Pessoa de Meia-Idade , Corpos de Inclusão Intranuclear/patologia , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/genética , Mutação , Distrofias Retinianas/complicações , Distrofias Retinianas/patologiaRESUMO
Browning of white adipose tissue (WAT) has been highlighted as a new possible therapeutic target for obesity, diabetes and lipid metabolic disorders, because WAT browning could increase energy expenditure and reduce adiposity. The new clusters of adipocytes that emerge with WAT browning have been named 'beige' or 'brite' adipocytes. Recent reports have indicated that the renin-angiotensin system (RAS) plays a role in various aspects of adipose tissue physiology and dysfunction. The biological effects of angiotensin II, a major component of RAS, are mediated by two receptor subtypes, angiotensin II type 1 receptor (AT1R) and type 2 receptor (AT2R). However, the functional roles of angiotensin II receptor subtypes in WAT browning have not been defined. Therefore, we examined whether deletion of angiotensin II receptor subtypes (AT1aR and AT2R) may affect white-to-beige fat conversion in vivo. AT1a receptor knockout (AT1aKO) mice exhibited increased appearance of multilocular lipid droplets and upregulation of thermogenic gene expression in inguinal white adipose tissue (iWAT) compared to wild-type (WT) mice. AT2 receptor-deleted mice did not show miniaturization of lipid droplets or alteration of thermogenic gene expression levels in iWAT. An in vitro experiment using adipose tissue-derived stem cells showed that deletion of the AT1a receptor resulted in suppression of adipocyte differentiation, with reduction in expression of thermogenic genes. These results indicate that deletion of the AT1a receptor might have some effects on the process of browning of WAT and that blockade of the AT1 receptor could be a therapeutic target for the treatment of metabolic disorders.
Assuntos
Adipócitos Marrons/citologia , Tecido Adiposo Branco/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/genética , Adipócitos Marrons/metabolismo , Tecido Adiposo Branco/citologia , Animais , Diferenciação Celular , Metabolismo Energético , Técnicas de Inativação de Genes , Masculino , Camundongos , Proteínas Mitocondriais , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , TermogêneseRESUMO
BACKGROUND: Angiotensin II type 2 (AT2) receptor stimulation could exert beneficial effects on vascular remodeling. Previously, we reported that AT2 receptor stimulation ameliorated insulin resistance in diabetic mice accompanied by PPARγ activation which also plays a variety of crucial roles in the vasculature. Therefore, this study aimed to investigate the vascular protective effect of the AT2 receptor with activation of PPARγ involving AT2 receptor-interacting protein (ATIP). METHODS AND RESULTS: Vascular injury was induced by polyethylene-cuff placement around the femoral artery in C57BL/6J mice. Treatment with compound 21 (C21), an AT2 receptor agonist, decreased neointimal formation, cell proliferation, and the mRNA levels of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF)-α, and interleukin-1ß, and phosphorylation of nuclear factor-kappa B, and increased PPARγ DNA-binding activity in the injured artery, whereas these inhibitory effects of C21 were attenuated by co-treatment with a PPARγ antagonist, GW9662. Treatment of vascular smooth muscle cells (VSMC) with C21 prepared from smAT2 transgenic mice, which highly express the AT2 receptor in VSMC, increased both PPARγ activity and its DNA-binding activity determined by dual-luciferase assay and electrophoresis mobility shift assay (EMSA), respectively. We observed that ATIP was involved in PPARγ complex formation, and that transfection of siRNA of ATIP1 attenuated the AT2 receptor-mediated increase in PPARγ activity in VSMC. In response to AT2 receptor stimulation, ATIP was translocated from the plasma membrane to the nucleus. CONCLUSIONS: Our results suggest a new mechanism by which AT2 receptor stimulation activates PPARγ, thereby resulting in amelioration of vascular intimal proliferation, and that ATIP plays an important role in AT2 receptor-mediated PPARγ activation.
Assuntos
Proteínas de Transporte/metabolismo , Neointima , PPAR gama/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Remodelação Vascular , Animais , Masculino , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/metabolismo , Sulfonamidas , TiofenosRESUMO
The possible counteracting effect of angiotensin (Ang)-converting enzyme (ACE)2/Ang-(1-7)/Mas axis against the ACE/Ang II/Ang II type 1 (AT1) receptor axis in blood pressure control has been previously described. We examined the possibility that this pathway might be involved in the anti-hypertensive effect of a newly developed AT1 receptor blocker (ARB), azilsartan, and compared azilsartan's effects with those of another ARB, olmesartan. Transgenic mice carrying the human renin and angiotensinogen genes (hRN/hANG-Tg) were given azilsartan or olmesartan. Systolic and diastolic blood pressure, as determined by radiotelemetry, were significantly higher in hRN/hANG-Tg mice than in wild-type (WT) mice. Treatment with azilsartan or olmesartan (1 or 5 mg kg(-1) per day) significantly decreased systolic and diastolic blood pressure, and the blood pressure-lowering effect of azilsartan was more marked than that of olmesartan. The urinary Na concentration decreased in an age-dependent manner in hRN/hANG-Tg mice. Administration of azilsartan or olmesartan increased urinary Na concentration, and this effect was weaker with olmesartan than with azilsartan. Azilsartan decreased ENaC-α mRNA expression in the kidney and decreased the ratio of heart to body weight. Olmesartan had a similar but less-marked effect. ACE2 mRNA expression was lower in the kidneys and hearts of hRN/hANG-Tg mice than in WT mice. This decrease in ACE2 mRNA expression was attenuated by azilsartan, but not by olmesartan. These results suggest that the hypotensive and anti-hypertrophic effects of azilsartan may involve activation of the ACE2/Ang-(1-7)/Mas axis with AT1 receptor blockade.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Angiotensina I/farmacologia , Anti-Hipertensivos/farmacologia , Benzimidazóis/farmacologia , Oxidiazóis/farmacologia , Fragmentos de Peptídeos/farmacologia , Peptidil Dipeptidase A/fisiologia , Proteínas Proto-Oncogênicas/fisiologia , Receptores Acoplados a Proteínas G/fisiologia , Enzima de Conversão de Angiotensina 2 , Animais , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/prevenção & controle , Canais Epiteliais de Sódio/genética , Imidazóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peptidil Dipeptidase A/genética , Proto-Oncogene Mas , Sódio/urina , Tetrazóis/farmacologiaRESUMO
Cross talk between the angiotensin-converting enzyme (ACE)/angiotensin II (Ang II)/Ang II type 1 (AT1) receptor axis and the ACE2/Ang-(1-7)/Mas axis plays a role in the pathogenesis of cardiovascular remodeling. Furthermore, possible stimulation of the Ang II type 2 (AT2) receptor by Ang-(1-7) has been highlighted as a new pathway. Therefore, we examined the possibility of whether the ACE2/Ang-(1-7)/Mas axis and Ang-(1-7)/AT2 receptor axis are involved in the inhibitory effects of AT1 receptor blockers on vascular remodeling. Wild-type, Mas-knockout, and AT2 receptor knockout mice were used in this study. Vascular injury was induced by polyethylene-cuff placement around the mouse femoral artery. Some mice were treated with azilsartan, an AT1 receptor blocker, or Ang-(1-7). Neointimal formation 2 weeks after cuff placement was more marked in Mas-knockout mice compared with wild-type mice. Treatment with azilsartan or Ang-(1-7) attenuated neointimal area, vascular smooth muscle cell proliferation, increases in the mRNA levels of monocyte chemoattractant protein-1, tumor necrosis factor-α, and interleukin-1ß, and superoxide anion production in the injured artery; however, these inhibitory effects of azilsartan and Ang-(1-7) were less marked in Mas-knockout mice. Administration of azilsartan or Ang-(1-7) attenuated the decrease in ACE2 mRNA and increased AT2 receptor mRNA but did not affect AT1 receptor mRNA or the decrease in Mas mRNA. The inhibitory effect of Ang-(1-7) on neointimal formation was less marked in AT2 receptor knockout mice compared with wild-type mice. These results suggest that blockade of the AT1 receptor by azilsartan could enhance the activities of the ACE2/Ang-(1-7)/Mas axis and ACE2/Ang-(1-7)/AT2 receptor axis, thereby inhibiting neointimal formation.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Angiotensina I/farmacologia , Regulação da Expressão Gênica , Fragmentos de Peptídeos/farmacologia , Peptidil Dipeptidase A/genética , RNA/genética , Receptor Tipo 2 de Angiotensina/genética , Resistência Vascular , Enzima de Conversão de Angiotensina 2 , Animais , Modelos Animais de Doenças , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Peptidil Dipeptidase A/metabolismo , RNA/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Receptor Tipo 2 de Angiotensina/metabolismo , Vasodilatadores/farmacologiaRESUMO
In order to investigate the role of angiotensin-converting enzyme 2 (ACE2) in cardiac development, we examined the effects of ACE2 deficiency on postnatal development of the heart using ACE2-knockout (ACE2KO) mice. Heart samples of wild type (WT; C57BL/6J) mice and ACE2KO mice were taken at 1, 4, and 10 weeks of age. In WT mice, expression of ACE2 mRNA increased from 1 week to 10 weeks. A similar increase was observed in immunostaining of ACE2 in the heart, in which ACE2 was strongly expressed in coronary arteries. Compared with WT mice, heart weight was greater in ACE2KO mice at 4 weeks, and coronary artery thickening and perivascular fibrosis were also already enhanced from 4 weeks. Consistent with the increase of fibrosis, cardiac expression of collagen and TIMP was higher, and expression of MMP was lower in ACE2KO mice at 4 weeks. In addition, TGF-ß mRNA was also higher, and lower expression of PPARγ mRNA was observed at 4 weeks in ACE2KO mice. These results suggest that ACE2 plays an important role in postnatal development of the heart, and that lack of ACE2 enhances coronary artery remodeling with an increase in perivascular fibrosis and cardiac hypertrophy already around the weaning period.
Assuntos
Cardiomegalia/genética , Doença da Artéria Coronariana/genética , Coração/crescimento & desenvolvimento , Peptidil Dipeptidase A/genética , Fatores Etários , Enzima de Conversão de Angiotensina 2 , Animais , Cardiomegalia/metabolismo , Cardiomegalia/patologia , Colágeno/genética , Colágeno/metabolismo , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Modelos Animais de Doenças , Feminino , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Coração/fisiologia , Masculino , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peptidil Dipeptidase A/metabolismo , Inibidor Tecidual de Metaloproteinase-1/genética , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Remodelação Ventricular/genéticaRESUMO
AIMS: The effects of AT(1) and AT(2) receptor deficiency on the intake and excretion of cholesterol were examined using atherosclerotic apolipoprotein E-null (ApoEKO) mice. MAIN METHODS: ApoEKO, AT(1)a/ApoEKO and AT(2)/ApoEKO mice received a high-cholesterol diet (HCD: 1.25% cholesterol) for 10 days before sampling. KEY FINDINGS: Plasma total cholesterol level was lower in AT(1)a/ApoEKO mice and higher in AT(2)/ApoEKO mice than in ApoEKO mice with a high cholesterol intake. In these mice, cholesterol content in feces was higher in AT(1)a/ApoEKO mice and lower in AT(2)/ApoEKO mice than in ApoEKO mice. Moreover, cholesterol content in bile tended to be higher in AT(1)a/ApoEKO mice and lower in AT(2)/ApoEKO mice than in ApoEKO mice, while a significant difference was observed only between AT(1)a/ApoEKO and AT(2)/ApoEKO mice. Cholesterol content and expression of HMG-CoA reductase and LDL receptor in liver were not different among the groups. Similar but weaker changes were also observed with a normal standard diet. Treatment with an AT(1) receptor blocker, irbesartan, increased cholesterol content in bile and tended to increase cholesterol excretion into feces in ApoEKO mice with HCD. SIGNIFICANCE: These results suggest that AT(1) and AT(2) receptor stimulation was involved in the regulation of cholesterol excretion into bile and feces, and that the regulation acted reciprocally in a cholesterol overload condition with HCD.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Apolipoproteínas E/fisiologia , Bile , Colesterol/metabolismo , Fezes , Receptor Tipo 2 de Angiotensina/deficiência , Acil Coenzima A/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Apolipoproteínas E/genética , Bile/química , Compostos de Bifenilo/farmacologia , Colesterol/sangue , Colesterol na Dieta/administração & dosagem , Fezes/química , Irbesartana , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Reação em Cadeia da Polimerase em Tempo Real , Receptor Tipo 2 de Angiotensina/genética , Receptores de LDL/biossíntese , Tetrazóis/farmacologiaRESUMO
Additional beneficial effects of angiotensin II type 1 (AT(1)) receptor blockers beyond AT(1) receptor blockade have been highlighted. Irbesartan is reported to act as an antagonist of the monocyte chemoattractant protein-1 (MCP-1) receptor, C-C chemokine receptor 2 (CCR2). We examined the possible synergistic effects of the combination of irbesartan with rosuvastatin on preventing vascular remodeling focusing on the MCP-1/CCR2 pathway. We observed that administration of irbesartan and CCR2 antagonist, propagermanium, at noneffective doses, decreased the neointima with a decrease in PCNA labeling index in the injured mouse femoral artery induced by cuff placement. We also observed that administration of a noneffective dose of rosuvastatin with propagermanium decreased the neointima area, suggesting that the inhibitory effect of rosuvastatin on neointima formation is at least partly attributable to blockade of the MCP-1/CCR2 pathway. Moreover, we demonstrated that the combination of irbesartan with rosuvastatin decreased neointima formation. MCP-1 mRNA level was significantly increased in injured femoral arteries, and administration of irbesartan with rosuvastatin decreased the mRNA levels of MCP-1, TNFα, and IL-1ß, and increased PPARγ mRNA expression. These results suggest that the synergistic inhibitory effects of irbesartan with rosuvastatin on neointima formation may involve attenuation of MCP-1/CCR2 signaling.
Assuntos
Compostos de Bifenilo/farmacologia , Quimiocina CCL2/efeitos dos fármacos , Artéria Femoral/efeitos dos fármacos , Fluorbenzenos/farmacologia , Pirimidinas/farmacologia , Receptores CCR2/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Tetrazóis/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Sinergismo Farmacológico , Artéria Femoral/lesões , Artéria Femoral/patologia , Germânio , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Irbesartana , Camundongos , Neointima/patologia , Neointima/prevenção & controle , Compostos Organometálicos/farmacologia , Propionatos , Rosuvastatina CálcicaRESUMO
We explored the roles of angiotensin-converting enzyme 2 (ACE2), angiotensin-(1-7), and Mas activation in angiotensin II type 1 receptor blockade-mediated attenuation of vascular remodeling. Vascular injury was induced by polyethylene-cuff placement around the mouse femoral artery. After cuff placement, the mRNA level of both ACE2 and Mas was markedly decreased in wild-type mice, whereas ACE mRNA was not changed. Immunostaining of ACE2 and Mas was observed mainly in the media and was reduced in the injured artery. Administration of angiotensin-(1-7) decreased neointimal formation after cuff placement, whereas administration of [D-Ala(7)] angiotensin-(1-7), a Mas antagonist, increased it. Consistent with these results, we also demonstrated that neointimal formation induced by cuff placement was further increased in ACE2 knockout mice. In angiotensin II type 1a receptor knockout mice, mRNA expression and immunostaining of ACE2 and Mas in the injured artery were greater, with less neointimal formation than in wild-type mice. Increased ACE2 expression in the injured artery was also observed by treatment of wild-type mice with an angiotensin II type 1 receptor blocker, olmesartan. These results suggested that activation of the ACE2-angiotensin-(1-7)-Mas axis is at least partly involved in the beneficial effects of angiotensin II type 1 receptor blockade on vascular remodeling.
Assuntos
Artéria Femoral/metabolismo , Peptidil Dipeptidase A/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Receptor Tipo 1 de Angiotensina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Angiotensina I/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Enzima de Conversão de Angiotensina 2 , Animais , Artéria Femoral/lesões , Artéria Femoral/fisiopatologia , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neointima/metabolismo , Neointima/fisiopatologia , Fragmentos de Peptídeos/farmacologia , Peptidil Dipeptidase A/genética , Proto-Oncogene Mas , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/genética , Receptor Tipo 1 de Angiotensina/genética , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/metabolismo , Túnica Íntima/fisiopatologiaRESUMO
BACKGROUND: Activity of renin substrate cleavage (renin-like activity) was measured in vitro in plasma samples obtained from healthy human volunteers. METHODS: Renin-like activity was determined using FRET (Fluorescence Resonance Energy Transfer) human renin substrate. Recombinant human renin and human plasma showed dose-dependent cleavage activity of FRET human renin substrate. RESULTS: Activity of recombinant human renin was completely inhibited by either a peptidergic or a non-peptidergic renin inhibitor. However, renin-like activity in human plasma was not inhibited by these renin inhibitors. In a mixture of recombinant renin and human plasma, renin inhibitors inhibited only that part of the activity caused by recombinant renin, while the activity in plasma still remained. Human plasma did not show cleavage activity of rat FRET renin substrate. Native human prorenin showed cleavage activity of human renin substrate. This activety was also completely inhibited by renin inhibitors. Immunoprecipitation with anti-renin or anti-prorenin antibodies did not reduce the activity in human plasma. Renin-like activity in human plasma was abolished by degeneration of protein when sample was heated to 95 degrees C. Activity of both recombinant renin and human plasma was significantly inhibited by a protease inhibitor cocktail. CONCLUSIONS: These results suggest that the activity of renin substrate cleavage in human plasma is not mainly caused by the renin or prorenin molecule, but probably by other proteases.
Assuntos
Inibidores de Proteases/farmacologia , Renina/antagonistas & inibidores , Renina/sangue , Adulto , Amidas/farmacologia , Angiotensinogênio/metabolismo , Animais , Precursores Enzimáticos/antagonistas & inibidores , Precursores Enzimáticos/metabolismo , Fumaratos/farmacologia , Humanos , Pessoa de Meia-Idade , Oligopeptídeos/farmacologia , Ratos , Proteínas Recombinantes/antagonistas & inibidores , Proteínas Recombinantes/sangue , Proteínas Recombinantes/metabolismo , Renina/metabolismo , Adulto JovemRESUMO
OBJECTIVE: Angiotensin-converting enzyme 2 (ACE2) generates angiotensin-(1-7) [Ang-(1-7)], a peptide highlighted as exerting a pivotal role in cardiovascular remodeling. Moreover, the ACE2/Ang-(1-7)/Mas axis directly activates endothelial nitric oxide (NO) synthase and NO generation in the heart. However, the role of ACE2 in cardiovascular remodeling induced by persistent inhibition of NO under chronic activation of the renin-angiotensin system (RAS) remains poorly understood. METHODS AND RESULTS: Chimeric hypertensive mice that exhibit activation of the human RAS were produced by mating human renin (hRN) and human angiotensinogen (hANG) transgenic mice. Persistent NO inhibition with NG-nitro-L-arginine methyl ester (L-NAME) was started at 8 weeks of age for 4 weeks. After administration of L-NAME, blood pressure (BP) markedly increased in the chimeric mice (hRN/hANG-Tg), whereas wild-type mice (C57BL/6J) showed little increase in BP. Cardiovascular remodeling with enhanced oxidative stress in hRN/hANG-Tg was markedly accelerated by NO inhibition compared with that in wild-type mice. Moreover, ACE2 mRNA expression and activity in cardiac tissue were markedly reduced in L-NAME-treated hRN/hANG-Tg. Co-administration of an angiotensin II type 1 (AT1) receptor blocker (ARB), olmesartan, inhibited L-NAME-induced cardiovascular remodeling and improved the reduction in cardiac ACE2. The preventive effect of olmesartan on cardiac hypertrophy was blunted by co-administration of a selective Ang-(1-7) antagonist, [D-Ala7]-Ang-(1-7). CONCLUSION: Our findings demonstrate that cardiovascular remodeling induced by persistent NO inhibition was enhanced in hRN/hANG-Tg. An ARB, olmesartan, blunted cardiac remodeling induced by NO inhibition with RAS activation partially through the ACE2/Ang-(1-7)/Mas axis in addition to directly through its classical ACE/Ang II/AT1 receptor axis-blocking action.
Assuntos
Cardiomegalia/patologia , Inibidores Enzimáticos/farmacologia , Óxido Nítrico Sintase/antagonistas & inibidores , Peptidil Dipeptidase A/fisiologia , Enzima de Conversão de Angiotensina 2 , Animais , Pressão Sanguínea , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , NADPH Oxidases/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Peptídeos/química , Peptidil Dipeptidase A/metabolismo , RNA Mensageiro/metabolismo , Sistema Renina-AngiotensinaRESUMO
This study explored the possible involvement of AT(2) receptor stimulation in the age-related gender difference in vascular remodeling of mouse femoral artery induced by cuff placement. In the young adult group of wild-type mice (10 weeks of age), the increase in DNA synthesis, neointimal formation, expression of chemokines, and superoxide anion production in the injured femoral artery were smaller in female than in male mice. These gender differences were smaller in the aged group (50-55 weeks of age) of wild-type mice, because vascular responses of female mice in the aged group were stronger than those in the young group. Treatment with 17ß-estradiol attenuated vascular remodeling in aged female mice. AT(2) receptor expression in the injured artery was higher in female than in male in the young group. AT(2) receptor expression in the injured artery of female mice was lower in the aged group than in the young group. Lack of AT(2) receptor increased neointimal formation in the aged group and reduced the inhibitory action of 17ß-estradiol in aged female mice. Our findings suggest a possibility that the change in AT(2) receptor stimulation by aging might be involved in the response to estrogen and improvement of vascular remodeling in the aged female group.
Assuntos
Estradiol/metabolismo , Artéria Femoral/patologia , Artéria Femoral/fisiologia , Neointima , Receptor Tipo 2 de Angiotensina/metabolismo , Túnica Íntima/patologia , Fatores Etários , Animais , Estradiol/uso terapêutico , Feminino , Artéria Femoral/efeitos dos fármacos , Masculino , Camundongos , Modelos Animais , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiopatologia , Neointima/metabolismo , Neointima/fisiopatologia , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Receptor Tipo 2 de Angiotensina/agonistas , Fatores Sexuais , Superóxidos/metabolismo , Túnica Íntima/efeitos dos fármacos , Túnica Íntima/metabolismo , Túnica Íntima/fisiologiaRESUMO
The effect of the PPARγ agonistic action of an AT(1) receptor blocker, irbesartan, on adipose tissue dysfunction was explored using atherosclerotic model mice. Adult male apolipoprotein E-deficient (ApoEKO) mice at 9 weeks of age were treated with a high-cholesterol diet (HCD) with or without irbesartan at a dose of 50mg/kg/day for 4 weeks. The weight of epididymal and retroperitoneal adipose tissue was decreased by irbesartan without changing food intake or body weight. Treatment with irbesartan increased the expression of PPARγ in white adipose tissue and the DNA-binding activity of PPARγ in nuclear extract prepared from adipose tissue. The expression of adiponectin, leptin and insulin receptor was also increased by irbesartan. These results suggest that irbesartan induced activation of PPARγ and improved adipose tissue dysfunction including insulin resistance.
Assuntos
Tecido Adiposo Branco/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/administração & dosagem , Aterosclerose/metabolismo , Compostos de Bifenilo/administração & dosagem , PPAR gama/agonistas , Tetrazóis/administração & dosagem , Adipócitos Brancos/efeitos dos fármacos , Adipócitos Brancos/metabolismo , Adipócitos Brancos/patologia , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/patologia , Animais , Apolipoproteínas E/genética , Aterosclerose/patologia , Biomarcadores/metabolismo , Contagem de Células , Colesterol na Dieta/administração & dosagem , DNA/metabolismo , Insulina/metabolismo , Insulina/farmacologia , Irbesartana , Masculino , Camundongos , Camundongos Knockout , PPAR gama/metabolismo , Ligação ProteicaRESUMO
BACKGROUND: The present study examined the inhibitory action of temporary treatment with an angiotensin type 1 (AT(1)) receptor blocker (ARB) on vascular remodeling using hypertensive mice with overexpression of the human renin (hRN) and angiotensinogen (hANG) genes. METHODS: hRN/hANG transgenic mice (hRN/hANG-Tg) were treated with an ARB, valsartan, from 4 weeks of age. In some mice, valsartan treatment was stopped at 8 weeks of age (temporary treatment). Inflammatory vascular injury was induced by polyethylene-cuff placement around the femoral artery at the age of 10 weeks. RESULTS: Compared with wild-type (WT) mice, hRN/hANG-Tg showed higher blood pressure (BP) and enhancement of oxidative stress and medial thickening even before cuff placement. Inflammatory vascular remodeling and oxidative stress after cuff placement were further enhanced in hRN/hANG-Tg. Temporary treatment with valsartan continuously lowered BP even after cessation of administration, and inhibited these changes. In contrast, administration of hydralazine lowered BP to a similar level to that with valsartan, but did not inhibit medial thickening and inflammatory vascular remodeling. In contrast to the valsartan treatment, BP immediately increased to the untreated level after cessation of hydralazine. CONCLUSIONS: These results indicate that temporary ARB treatment leads to prolonged effect of BP lowering and prevents vascular remodeling in hypertensive mice induced by activation of the human renin-angiotensin system. The inhibitory action of valsartan is not due to the BP lowering but is at least in part due to a decrease in oxidative stress and inflammation.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Vasos Sanguíneos/patologia , Hipertensão/tratamento farmacológico , Tetrazóis/uso terapêutico , Valina/análogos & derivados , Angiotensinogênio/genética , Animais , Artérias/patologia , Modelos Animais de Doenças , Hidralazina/uso terapêutico , Hipertensão/patologia , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidases/fisiologia , Neointima/patologia , Estresse Oxidativo/efeitos dos fármacos , Renina/genética , Valina/uso terapêutico , ValsartanaRESUMO
BACKGROUND: To explore the metabolic actions of nifedipine on diabetes, we examined glucose intolerance and white adipose tissue changes in type 2 diabetic KK-A(y) mice. METHODS: Male KK-A(y) mice were treated with nifedipine (1.5 mg/kg/day in lab chow) for 5 weeks, which did not affect blood pressure or feeding of KK-A(y) mice. RESULTS: After treatment with nifedipine, body weight tended to decrease and the weight of white adipose tissue was reduced. Without food restriction, nifedipine decreased plasma insulin level, while plasma glucose level tended to decrease. In oral glucose tolerance test, nifedipine suppressed the increase in glucose level after a glucose load without affecting plasma insulin concentration. Nifedipine also improved the result of insulin tolerance test. In white adipose tissue, nifedipine increased adipocyte number and the expression of peroxisome proliferator-activated receptor-γ (PPARγ) and adipocyte fatty acid-binding protein related to adipocyte differentiation. In addition, expression of adiponectin, insulin receptor, insulin receptor substrate-1, and glucose transporter type-4 was also increased by nifedipine. Nifedipine also increased the expression of NO synthase in white adipose tissue. Nifedipine did not affect expression of angiotensin II type 1 (AT1) and type 2 (AT2) receptors in white adipose tissue. Such changes in white adipose tissue were apparent in retroperitoneal adipose tissue. Nifedipine did not change the expression of angiotensin receptors, renin receptor, and angiotensinogen in white adipose tissue. Moreover, nifedipine attenuated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity and increased superoxide dismutase (SOD) activity in white adipose tissue. CONCLUSION: These results suggest that nifedipine can enhance insulin sensitivity and reduce white adipose tissue, possibly related to stimulation of adipocyte differentiation.
Assuntos
Adipócitos/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Glicemia/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Resistência à Insulina , Nifedipino/farmacologia , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Adiponectina/metabolismo , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/fisiopatologia , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/fisiopatologia , Modelos Animais de Doenças , Proteínas de Ligação a Ácido Graxo/metabolismo , Teste de Tolerância a Glucose , Transportador de Glucose Tipo 4/metabolismo , Insulina/sangue , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , NADPH Oxidases/metabolismo , Óxido Nítrico Sintase/metabolismo , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/metabolismo , Receptores de Angiotensina/metabolismo , Superóxido Dismutase/metabolismo , Fatores de Tempo , Redução de PesoRESUMO
OBJECTIVE: The renin-angiotensin system affects insulin sensitivity mainly through the angiotensin II type 1 receptor. In this study, the effects of renin inhibition on insulin resistance and adipose tissue dysfunction were explored in type 2 diabetic KK-A(y) mice. METHODS AND RESULTS: Male KK-A mice were treated with a direct renin inhibitor, aliskiren, administered subcutaneously at a dose of 50 mg/kg per day for 14 days using an osmotic minipump. This dose of aliskiren strongly inhibited plasma renin activity and lowered blood pressure about 17% in KK-A(y) mice. Aliskiren decreased body weight and plasma glucose level, and increased plasma insulin level in a fed condition. Aliskiren also lowered the plasma levels of cholesterol, fatty acids and triglycerides. In the oral glucose tolerant test, the plasma glucose elevation after glucose load was reduced by aliskiren, without a significant change in insulin level. Insulin tolerance test showed that aliskiren enhanced insulin's effect on plasma glucose. Aliskiren also reduced the epididymal adipose tissue mass by 25% and retroperitoneal adipose tissue mass by 35%. In adipose tissue, expression of the insulin receptor was not changed by aliskiren; however, expression of insulin receptor substrate-1, glucose transporter type 4, adiponectin, peroxisome proliferator-activated receptor-gamma and CCAAT/enhancer-binding proteindelta was increased by aliskiren. Moreover, NADPH oxidase activity and expression of inflammatory factors were reduced in adipose tissue. Aliskiren increased the pancreatic beta-cell area in KK-A(y) mice. CONCLUSION: These results suggest that renin inhibition by aliskiren improved insulin resistance and adipose tissue dysfunction in type 2 diabetic mice through an increase in insulin sensitivity, insulin secretion and adipocyte differentiation, and a reduction of oxidative stress.
Assuntos
Tecido Adiposo/efeitos dos fármacos , Amidas/farmacologia , Diabetes Mellitus Tipo 2/metabolismo , Fumaratos/farmacologia , Resistência à Insulina/fisiologia , Renina/antagonistas & inibidores , Adiponectina/metabolismo , Adiponectina/farmacologia , Adiponectina/uso terapêutico , Tecido Adiposo/metabolismo , Tecido Adiposo/fisiopatologia , Animais , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose/metabolismo , Glucose/farmacologia , Glucose/uso terapêutico , Transportador de Glucose Tipo 4/metabolismo , Insulina/sangue , Insulina/metabolismo , Insulina/farmacologia , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Camundongos , PPAR gama/metabolismo , PPAR gama/farmacologia , PPAR gama/uso terapêutico , Renina/metabolismo , Renina/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacosRESUMO
We studied the energy metabolism of cataracts induced by ultraviolet (UV) irradiation by observing metabolic changes in lenses using 31P-, 1H-, and 13C-nuclear magnetic resonance (NMR) spectroscopy. % of hexose monophosphate shunt flux activity increased over time. The lactate/glucose ratio in the UV irradiation group decreased to about half of that of the corresponding control group (11.6 +/- 2.0% vs. 20.7 +/- 1.7%, respectively, p < 0.05) after 10 h of irradiation and to about 30% of that of the control group (25 +/- 2% vs. 92 +/- 6%, respectively) after 24 h. The adenosine triphosphate (ATP) level significantly decreased after 3 h of irradiation (86 +/- 29%, p < 0.05) and continuously decreased to 68 +/- 33% (p < 0.01) after 10 h of irradiation and 26 +/- 2% (p < 0.01) after 24 h of irradiation. Conversely, a significant increase in inorganic phosphate (Pi) was observed after 1 h of irradiation (111 +/- 26%, p < 0.05), and the Pi level gradually increased to 140 +/- 28% after 10 h of irradiation (p < 0.01) and 207 +/- 26% after 24 h (p < 0.01). A significant decrease in alpha-glycerophosphate was noted after 24 h (38 +/- 13%, p < 0.01). The ribose-5-phosphate (R-5-P) level gradually increased after irradiation to 128 +/- 13% (p < 0.05) after 10 h and 141 +/- 21% after 24 h (p < 0.01). The results suggest that of these metabolic changes a marked decline in glycolytic production of ATP, which inhibits membrane metabolism, may be an important cataract-inducing factor following UV irradiation.
Assuntos
Catarata/etiologia , Catarata/metabolismo , Cristalino/metabolismo , Raios Ultravioleta , Trifosfato de Adenosina/metabolismo , Animais , Metabolismo Energético , Glicerofosfatos/metabolismo , Cristalino/efeitos da radiação , Espectroscopia de Ressonância Magnética , Via de Pentose Fosfato/fisiologia , Fosfatos/metabolismo , CoelhosRESUMO
The effects of the coadministration of pravastatin and an angiotensin type 1 (AT(1)) receptor blocker, olmesartan, on glucose intolerance were examined using type II diabetic mice. Male KK-A(y) mice (8 weeks of age) were treated with pravastatin and/or olmesartan for 2 weeks. An oral glucose tolerance test (OGTT) was performed with an administration of 2 g kg(-1) glucose. Tissue glucose uptake was determined using 2-[(3)H]deoxyglucose. The treatment of mice with pravastatin attenuated the increase in the plasma glucose level during OGTT in a dose-dependent manner, without affecting the plasma insulin level. Pravastatin increased glucose uptake in insulin-sensitive tissue such as the skeletal muscle and adipose tissue after treatment at 5-20 mg kg(-1) day(-1) for 2 weeks, but not at 1 mg kg(-1) day(-1). The combination of a noneffective dose of pravastatin (1 mg kg(-1) day(-1)) and a noneffective dose of olmesartan (0.5 mg kg(-1) day(-1)) synergistically improved OGTT without affecting the plasma insulin level. This combination also increased 2-[(3)H]deoxyglucose uptake in the skeletal muscle and adipose tissue. The effects of pravastatin or olmesartan on OGTT and tissue 2-[(3)H]deoxyglucose uptake were significantly enhanced by an antioxidant, tempol, whereas the effects of a pravastatin-olmesartan combination were not further enhanced by tempol. These results indicate that the combination of pravastatin and olmesartan synergistically improves glucose intolerance through an increase in tissue glucose uptake. The effects seem to be mediated by an increase in insulin sensitivity through the inhibition of oxidative stress.
Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Intolerância à Glucose/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Imidazóis/uso terapêutico , Pravastatina/uso terapêutico , Tetrazóis/uso terapêutico , Animais , Antimetabólitos , Antioxidantes/farmacologia , Glicemia/metabolismo , Óxidos N-Cíclicos/farmacologia , Desoxiglucose , Quimioterapia Combinada , Intolerância à Glucose/genética , Insulina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos , Estresse Oxidativo/efeitos dos fármacos , Marcadores de SpinRESUMO
BACKGROUND: Previous reports indicated that blockade of AT(1) receptor stimulation attenuated adipocyte dysfunction. However, the effects of AT(2) receptor stimulation on adipose tissue were not yet clear. In the present study, we examined the adipose tissue dysfunction in atherosclerotic apolipoprotein E knockout (ApoEKO) mice with AT(2) receptor deficiency. METHODS: Male ApoEKO and AT(2) receptor/ApoE knockout (AT(2)/ApoEKO) mice at 6 weeks of age were treated with a normal diet or a high-cholesterol diet (HCD: 1.25% cholesterol). Markers for adipocyte differentiation and inflammation in adipose tissue were assayed with real-time reverse-transcription-PCR and western blot. RESULTS: Compared with ApoEKO mice, AT(2)/ApoEKO mice with a normal diet showed only a decrease in expression of adiponectin and CCAAT/enhancer binding protein delta (C/EBPdelta) in epididymal adipose tissue without changes in body weight, adipose tissue weight, and adipocyte number even at 6 months of age. After HCD for 4 weeks, the weight of both epididymal and retroperitoneal adipose tissue in AT(2)/ApoEKO mice was greater than that in ApoEKO mice without a change in body weight. Plasma concentrations of cholesterol and fatty acids were higher in AT(2)/ApoEKO mice than in ApoEKO mice. In adipose tissue of AT(2)/ApoEKO mice, the adipocyte number was decreased and the expression of peroxisome proliferator-activated receptor gamma (PPARgamma), C/EBPalpha, and aP2 was lower than that in ApoEKO mice, in association with an increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity. CONCLUSIONS: These results suggest that AT(2) receptor stimulation in adipose tissue is involved in the improvement of adipocyte differentiation and adipose tissue dysfunction in atherosclerotic model.
Assuntos
Adipócitos/fisiologia , Aterosclerose/patologia , Receptor Tipo 2 de Angiotensina/deficiência , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/patologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 2 de Angiotensina II , Animais , Apolipoproteínas E/genética , Aterosclerose/fisiopatologia , Contagem de Células , Diferenciação Celular/fisiologia , Colesterol na Dieta/administração & dosagem , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Camundongos , Camundongos Knockout , NADPH Oxidases/metabolismo , Receptor Tipo 2 de Angiotensina/fisiologia , Tetrazóis/farmacologia , Valina/análogos & derivados , Valina/farmacologia , ValsartanaRESUMO
BACKGROUND AND PURPOSE: We examined the possibility that activation of the human brain renin-angiotensin system is involved in enhancement of ischemic brain damage using chimeric transgenic mice with human renin (hRN) and human angiotensinogen (hANG) genes. METHODS: Chimeric (hRN/hANG-Tg) mice were generated by mating of hRN and hANG transgenic mice. Permanent occlusion of the middle cerebral artery (MCA) by an intraluminal filament technique induced focal ischemic brain lesions. RESULTS: hRN/hANG-Tg mice showed higher angiotensin II levels in the plasma and brain. The ischemic brain area at 24 hours after MCA occlusion was significantly enlarged in hRN/hANG-Tg mice with an enhanced neurological deficit compared to that in wild-type, hRN-Tg and hANG-Tg mice. The reduction of cerebral blood flow in the periphery region of the MCA territory after MCA occlusion was markedly exaggerated in hRN/hANG-Tg mice. Superoxide anion production in the brain and arteries was also increased significantly in hRN/hANG-Tg mice even before MCA occlusion and was further enhanced after MCA occlusion. Treatment with an AT(1) receptor blocker, valsartan (3.0 mg/kg per day), for 2 weeks significantly reduced the ischemic brain area and improved the neurological deficit after MCA occlusion in hRN/hANG-Tg mice, similar to those in wild-type, hRN-Tg, and hANG-Tg mice, with restoration of cerebral blood flow in the peripheral region and decreases in superoxide anion production and blood pressure. CONCLUSIONS: These results indicate that activation of the human renin-angiotensin system exaggerates ischemic brain damage mainly through stimulation of the AT(1) receptor and marked reduction of cerebral blood flow and enhanced oxidative stress.