RESUMEN
The Ang II type 1 receptor (AT1R)-associated protein (ATRAP/Agtrap) is a molecule specifically interacting with the carboxyl- terminal domain of AT1R. The results of in vitro studies showed that ATRAP suppresses Ang II-mediated pathological responses in cardiovascular cells by promoting AT1R internalization. With respect to the tissue distribution and regulation of ATRAP expression in vivo, ATRAP is broadly expressed in many tissues as is AT1R. Accumulating evidence indicates that a tissue-specific regulatory balancing of ATRAP and AT1R expression may be involved in the modulation of AT1R signaling at local tissue sites and also in the pathophysiology of hypertension and its associated end-organ injury. Furthermore, the activation of ATRAP in transgenic-models inhibited inflammatory vascular remodeling and cardiac hypertrophy in response to Ang II stimulation. These results suggest the clinical potential benefit of an ATRAP activation strategy in the treatment of hypertension and related organ injury.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Proteínas Adaptadoras Transductoras de Señales/análisis , Proteínas Adaptadoras Transductoras de Señales/química , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Células Cultivadas , Regulación de la Expresión Génica , Humanos , Estructura Terciaria de Proteína , Receptor de Angiotensina Tipo 1/fisiologíaRESUMEN
OBJECTIVE: We previously showed that the molecule interacting with Ang II type 1 receptor (AT1R), ATRAP, promotes AT1R internalization and attenuates AT1R-mediated pathological responses. In this study we examined whether the regulation of renal ATRAP expression is related to the development of salt-induced hypertension and renal injury as well as to the beneficial effects of AT1R blockade. METHODS AND RESULTS: Dahl Iwai salt-sensitive hypertensive and Dahl Iwai salt-resistant rats were divided into six groups for the administration of vehicle or olmesartan either continuously from 3 to 16 weeks, or transiently from weaning to puberty (3-10 weeks), and fed high salt diet from 6 to 16 weeks. In Dahl Iwai salt-sensitive rats, not only continuous, but also prepubertal olmesartan treatment improved hypertension at 15 weeks. Renal ATRAP expression was suppressed in vehicle-treated Dahl Iwai salt-sensitive rats, concomitant with up-regulation of renal oxidative stress, inflammation and fibrosis-related markers such as p22phox, TGF-ß, fibronectin, monocyte chemotactic protein-1 and type 1 collagen. However, prepubertal as well as continuous olmesartan treatment recovered the suppressed renal ATRAP expression and inhibited the renal activation of p22phox, TGF-ß, fibronectin, MCP-1 and type 1 collagen. In Dahl Iwai salt-resistant rats, such suppression of renal ATRAP expression or induction of renal pathological responses by salt loading was not observed. CONCLUSIONS: These results indicate that prepubertal transient blockade of AT1R signaling exerts a long-term therapeutic effect on salt-induced hypertension and renal injury in Dahl Iwai salt-sensitive rats, partly through a sustained enhancement of renal ATRAP expression, thereby suggesting ATRAP a novel molecular target in salt-induced hypertension and renal injury.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Hipertensión/tratamiento farmacológico , Receptores de Angiotensina/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Hipertensión/etiología , Hipertensión/fisiopatología , Imidazoles/farmacología , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Endogámicas Dahl , Receptor de Angiotensina Tipo 1/metabolismo , Receptor de Angiotensina Tipo 2/metabolismo , Renina/metabolismo , Maduración Sexual , Cloruro de Sodio Dietético/administración & dosificación , Tetrazoles/farmacologíaRESUMEN
Presently hypertensive patients with chronic kidney disease (CKD) particularly diabetic nephropathy are increasing in number, and cardiovascular and renal complications are the most common cause of death in these patients. The control of blood pressure (BP) is an important issue in cardiovascular and renal protection in hypertensive patients with CKD. Although hypertension is usually diagnosed based on measurements of BP recorded during a visit to a physician, that is, office BP, several studies have shown that target organ damage and prognosis are more closely associated with ambulatory BP than with office BP. It should be important to achieve the target absolute BP levels in hypertensive patients obtained either by office or home measurements or by ambulatory recordings for the cardiovascular and renal protection. Noninvasive techniques for measuring ambulatory BP have allowed BP to be monitored during both day and night. Additionally, ambulatory BP monitoring can provide information on circadian BP variation and short-term BP variability, which is suggested to be associated with cardiovascular and renal morbidity and mortality. This review will briefly summarize the emerging concept of anti-hypertensive therapy based on ambulatory BP profile in hypertensive patients with CKD.
RESUMEN
ATRAP [ANG II type 1 receptor (AT1R)-associated protein] is a molecule which directly interacts with AT1R and inhibits AT1R signaling. The aim of this study was to examine the effects of continuous ANG II infusion on the intrarenal expression and distribution of ATRAP and to determine the role of AT1R signaling in mediating these effects. C57BL/6 male mice were subjected to vehicle or ANG II infusions at doses of 200, 1,000, or 2,500 ng·kg(-1)·min(-1) for 14 days. ANG II infusion caused significant suppression of ATRAP expression in the kidney but did not affect ATRAP expression in the testis or liver. Although only the highest ANG II dose (2,500 ng·kg(-1)·min(-1)) provoked renal pathological responses, such as an increase in the mRNA expression of angiotensinogen and the α-subunit of the epithelial sodium channel, ANG II-induced decreases in ATRAP were observed even at the lowest dose (200 ng·kg(-1)·min(-1)), particularly in the outer medulla of the kidney, based on immunohistochemical staining and Western blot analysis. The decrease in renal ATRAP expression by ANG II infusion was prevented by treatment with the AT1R-specific blocker olmesartan. In addition, the ANG II-mediated decrease in renal ATRAP expression through AT1R signaling occurred without an ANG II-induced decrease in plasma membrane AT1R expression in the kidney. On the other hand, a transgenic model increase in renal ATRAP expression beyond baseline was accompanied by a constitutive reduction of renal plasma membrane AT1R expression and by the promotion of renal AT1R internalization as well as the decreased induction of angiotensinogen gene expression in response to ANG II. These results suggest that the plasma membrane AT1R level in the kidney is modulated by intrarenal ATRAP expression under physiological and pathophysiological conditions in vivo.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Angiotensina II/farmacología , Riñón/fisiología , Proteínas Adaptadoras Transductoras de Señales/genética , Angiotensinógeno/biosíntesis , Animales , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Peso Corporal/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Canales Epiteliales de Sodio/biosíntesis , Inmunohistoquímica , Riñón/efectos de los fármacos , Riñón/metabolismo , Médula Renal/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , NADPH Oxidasa 4 , NADPH Oxidasas/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
We cloned a novel molecule interacting with angiotensin II type 1 receptor, which we named ATRAP (for angiotensin II type 1 receptor-associated protein). Previous in vitro studies showed that ATRAP significantly promotes constitutive internalization of the angiotensin II type 1 receptor and further attenuates angiotensin II-mediated hypertrophic responses in cardiomyocytes. The present study was designed to investigate the putative functional role of ATRAP in cardiac hypertrophy by angiotensin II infusion in vivo. We first examined the effect of angiotensin II infusion on endogenous ATRAP expression in the heart of C57BL/6J wild-type mice. The angiotensin II treatment promoted cardiac hypertrophy, concomitant with a significant decrease in cardiac ATRAP expression, but without significant change in cardiac angiotensin II type 1 receptor expression. We hypothesized that a downregulation of the cardiac ATRAP to angiotensin II type 1 receptor ratio is involved in the pathogenesis of cardiac hypertrophy. To examine this hypothesis, we next generated transgenic mice expressing ATRAP specifically in cardiomyocytes under control of the alpha-myosin heavy chain promoter. In cardiac-specific ATRAP transgenic mice, the development of cardiac hypertrophy, activation of p38 mitogen-activated protein kinase, and expression of hypertrophy-related genes in the context of angiotensin II treatment were completely suppressed, in spite of there being no significant difference in blood pressure on radiotelemetry between the transgenic mice and littermate control mice. These results demonstrate that cardiomyocyte-specific overexpression of ATRAP in vivo abolishes the cardiac hypertrophy provoked by chronic angiotensin II infusion, thereby suggesting ATRAP to be a novel therapeutic target in cardiac hypertrophy.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Angiotensina II/efectos adversos , Cardiomegalia/prevención & control , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/uso terapéutico , Animales , Presión Sanguínea/efectos de los fármacos , Peso Corporal , Cardiomegalia/patología , Cardiomegalia/fisiopatología , Genotipo , Frecuencia Cardíaca/efectos de los fármacos , Imidazoles/uso terapéutico , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , ARN/genética , ARN/aislamiento & purificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tetrazoles/uso terapéuticoRESUMEN
Blood pressure (BP) variability is calculated as the standard deviation of ambulatory BP. Blood pressure variability is associated with the cardiovascular morbidity; however whether it is related to target organ damage is controversial. In this study we examined a possible relationship between the BP variability and left ventricular hypertrophy (LVH), and between BP variability and brachial-ankle pulse wave velocity (baPWV). The present study was conducted on 111 consecutive Japanese hypertensive patients who were hospitalized for the educational program in our hospital under stable sodium chloride intake (6 g/day). Blood pressure measurements were at 30-minute intervals all day. In a multivariable analysis adjusted with confounding factor, LVH was associated with 24-hour systolic BP (SBP), 24 hour diastolic BP (DBP), daytime SBP, daytime DBP, nighttime SBP, and nighttime DBP. Additionally, nighttime DBP variability was related to LVH. By the same method, baPWV as a dependent variable was related to 24-hour SBP and nighttime SBP. Furthermore, nighttime SBP variability was concerned with baPWV. The LVH was associated with not only BP level but also with nighttime DBP variability. The baPWV was also related not only to BP level but also to nighttime SBP variability.
Asunto(s)
Índice Tobillo Braquial , Determinación de la Presión Sanguínea/métodos , Presión Sanguínea , Hipertensión/fisiopatología , Hipertrofia Ventricular Izquierda/fisiopatología , Anciano , Monitoreo Ambulatorio de la Presión Arterial/métodos , Ritmo Circadiano , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/diagnóstico , Hipertrofia Ventricular Izquierda/diagnóstico , Hipertrofia Ventricular Izquierda/etiología , Pacientes Internos , Persona de Mediana Edad , Análisis Multivariante , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la EnfermedadRESUMEN
AIMS: In this study, we examined whether addition of an angiotensin II type 1 receptor blocker (ARB), candesartan or valsartan, to conventional antihypertensive treatment could improve blood pressure (BP) variability in hypertensive patients on peritoneal dialysis. METHODS: 45 hypertensive patients on chronic peritoneal dialysis therapy were randomly assigned to the ARB treatment groups either by candesartan (n = 15) or valsartan (n = 15), or the control group (n = 15). At baseline and 6 months after the treatment, 24-hour ambulatory BP monitoring, echocardiography, and measurement of brachial-ankle pulse wave velocity (baPWV) were performed. RESULTS: After the 6 months of treatment, 24-hour ambulatory BP values were similarly decreased in both the control group and ARB groups. However, short-term BP variability assessed on the basis of the standard deviation of 24-hour ambulatory BP was significantly decreased in the ARB groups, but remained unchanged in the control group. Furthermore, parameters of cardiovascular remodeling assessed by natriuretic peptides, echocardiography, and baPWV were significantly improved in the ARB groups but not in the control group. CONCLUSION: ARB treatment and control antihypertensive treatment similarly controlled 24-hour ambulatory BP values in hypertensive patients on peritoneal dialysis. However, ARB treatment is beneficial for the suppression of pathological cardiovascular remodeling with a decrease in BP variability.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Antihipertensivos/farmacología , Bencimidazoles/uso terapéutico , Presión Sanguínea/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Fallo Renal Crónico/terapia , Diálisis Peritoneal Ambulatoria Continua , Tetrazoles/farmacología , Tetrazoles/uso terapéutico , Valina/análogos & derivados , Remodelación Ventricular/efectos de los fármacos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Antihipertensivos/uso terapéutico , Bencimidazoles/administración & dosificación , Biomarcadores , Compuestos de Bifenilo , Bloqueadores de los Canales de Calcio/administración & dosificación , Bloqueadores de los Canales de Calcio/uso terapéutico , Ritmo Circadiano/efectos de los fármacos , Quimioterapia Combinada , Femenino , Frecuencia Cardíaca/efectos de los fármacos , Humanos , Hipertensión/complicaciones , Hipertensión/fisiopatología , Fallo Renal Crónico/complicaciones , Masculino , Persona de Mediana Edad , Péptidos Natriuréticos/sangre , Pulso Arterial , Tetrazoles/administración & dosificación , Valina/farmacología , Valina/uso terapéutico , ValsartánRESUMEN
We examined risk factors for coronary heart disease (CHD) by ambulatory blood pressure (BP) monitoring in 72 diabetic hypertensives who were hospitalized for the educational program. The patients were divided into two groups (CHD group, 19 subjects; and non-CHD group, 53 subjects) along with or without co-existing CHD. On ambulatory BP monitoring, no significant differences were found between the groups regarding BP values through the day. However, the CHD group had a significantly greater BP variability than non-CHD group. The result of logistic regression analysis demonstrated that nighttime systolic BP variability was an independent risk factor for CHD.
Asunto(s)
Monitoreo Ambulatorio de la Presión Arterial , Presión Sanguínea/fisiología , Ritmo Circadiano/fisiología , Enfermedad Coronaria/epidemiología , Complicaciones de la Diabetes/complicaciones , Hipertensión/complicaciones , Anciano , Enfermedad Coronaria/fisiopatología , Estudios Transversales , Complicaciones de la Diabetes/fisiopatología , Femenino , Humanos , Hipertensión/fisiopatología , Modelos Logísticos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Factores de RiesgoRESUMEN
We previously cloned a novel molecule interacting with angiotensin II (Ang II) type 1 receptor protein (ATRAP) and showed it to be an endogenous inhibitor of Ang II type 1 receptor signaling in cardiovascular cells. In this study, we tested a hypothesis that the balance of tissue expression of ATRAP and Ang II type 1 receptor is regulated in a tissue-specific manner during the development of hypertension and related cardiac hypertrophy. Concomitant with blood pressure increase and cardiac hypertrophy in spontaneously hypertensive rats, there was a constitutive decrease in the ratio of cardiac expression of ATRAP to Ang II type 1 receptor. However, treatment with olmesartan, an Ang II type 1 receptor-specific antagonist, either at a depressor or subdepressor dose, recovered the suppressed cardiac ATRAP to Ang II type 1 receptor ratio, which was accompanied by a decrease in Ang II type 1 receptor density, an inhibition of p38 mitogen-activated protein kinase activity, and a regression of cardiac hypertrophy. Furthermore, Ang II stimulation suppressed the ATRAP to Ang II type 1 receptor ratio with hypertrophic responses in both the cardiomyocytes and rat hearts. These findings show a tissue-specific regulatory balancing of the expression of ATRAP and Ang II type 1 receptor during the development of hypertension and cardiac remodeling and further suggest that the upregulation of the tissue ATRAP to Ang II type 1 receptor ratio may be one of the therapeutic benefits of olmesartan beyond its blood pressure-lowering effect.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Expresión Génica , Hipertensión/tratamiento farmacológico , Hipertrofia Ventricular Izquierda/prevención & control , Imidazoles/uso terapéutico , Receptor de Angiotensina Tipo 1/genética , Tetrazoles/uso terapéutico , Bloqueadores del Receptor Tipo 1 de Angiotensina II/administración & dosificación , Animales , Presión Sanguínea , Western Blotting , Modelos Animales de Enfermedad , Ventrículos Cardíacos/metabolismo , Hipertensión/complicaciones , Hipertensión/genética , Hipertrofia Ventricular Izquierda/etiología , Hipertrofia Ventricular Izquierda/genética , Imidazoles/administración & dosificación , Masculino , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1/biosíntesis , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Tetrazoles/administración & dosificación , Remodelación Ventricular/efectos de los fármacosRESUMEN
We have recently cloned a novel molecule that interacts with the angiotensin II type 1 receptor (AT1R)-associated protein (ATRAP). In this study, we tested the hypothesis that ATRAP modulates angiotensin II-induced responses in vascular smooth muscle cells. The results of immunoprecipitation and bioluminescence resonance energy transfer assay demonstrated a direct interaction between ATRAP and AT1R at baseline and showed that angiotensin II enhanced the interaction of these proteins >2-fold. The results of immunofluorescence analysis also demonstrated that >65% of ATRAP constitutively colocalized with an endosome marker. Although only 36% of ATRAP colocalized with AT1R at baseline, angiotensin II enhanced the colocalization of these molecules and made 92% of ATRAP colocalize with AT1R on a quantitative fluorescence analysis. Overexpression of ATRAP by adenoviral transfer decreased the cell surface AT1R number from 4.33 to 2.13 fmol/10(6) cells at baseline and from 3.04 to 1.26 fmol/10(6) cells even after removal of angiotensin II. ATRAP also suppressed angiotensin II-mediated increases in c-fos gene transcription and transforming growth factor-beta production. Furthermore, this suppression was accompanied by inhibition of angiotensin II-induced activation of 5-bromodeoxyuridine incorporation. Finally, ATRAP knockdown by small-interference RNA activated angiotensin II-induced c-fos gene expression, which was effectively inhibited by valsartan, an AT1R-specific antagonist. These results indicate that ATRAP promotes internalization of AT1R and attenuates the angiotensin II-mediated c-fos-transforming growth factor-beta pathway and proliferative response in vascular smooth muscle cells, suggesting a novel strategy to inhibit vascular fibrosis and remodeling through a novel and specific blockade of AT1R signaling.
Asunto(s)
Músculo Liso Vascular/fisiología , Receptor de Angiotensina Tipo 1/metabolismo , Receptores de Angiotensina/fisiología , Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Animales , Células Cultivadas , Transferencia Resonante de Energía de Fluorescencia , Técnicas de Transferencia de Gen , Inmunoprecipitación , Músculo Liso Vascular/citología , Músculo Liso Vascular/efectos de los fármacos , Unión Proteica , Proteínas Proto-Oncogénicas c-fos/metabolismo , ARN Interferente Pequeño/farmacología , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1/efectos de los fármacos , Receptor de Angiotensina Tipo 1/genética , Receptores de Angiotensina/genética , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Tetrazoles/farmacología , Transcripción Genética/efectos de los fármacos , Valina/análogos & derivados , Valina/farmacología , ValsartánRESUMEN
We cloned a novel molecule, AT1 receptor-associated protein (ATRAP), which is expressed in many tissues but specifically interacts with the AT1 receptor carboxyl-terminal. In the kidney, ATRAP was broadly distributed along the renal tubules; salt intake modulated its expression. In cardiovascular cells, angiotensin II (Ang II) stimulation made ATRAP co-localized with AT1 receptor in cytoplasm; ATRAP overexpression decreased cell surface AT1 receptor. In downstream signaling pathways, ATRAP suppressed Ang II-induced phosphorylation of mitogen-activated protein kinase, activation of c-fos gene transcription, and enhancement of amino acid or bromodeoxyuridine incorporation in cardiovascular cells. Thus, cardiovascular ATRAP may promote AT1 receptor internalization and attenuate Ang II-mediated cardiovascular remodeling. We would expect ATRAP to become a new therapeutic target molecule to treat and prevent cardiovascular remodeling in hypertension.