RESUMEN
Primary sclerosing cholangitis (PSC) is characterized by progressive biliary inflammation and fibrosis. Although gut commensals are associated with PSC, their causative roles and therapeutic strategies remain elusive. Here we detect abundant Klebsiella pneumoniae (Kp) and Enterococcus gallinarum in fecal samples from 45 PSC patients, regardless of intestinal complications. Carriers of both pathogens exhibit high disease activity and poor clinical outcomes. Colonization of PSC-derived Kp in specific pathogen-free (SPF) hepatobiliary injury-prone mice enhances hepatic Th17 cell responses and exacerbates liver injury through bacterial translocation to mesenteric lymph nodes. We developed a lytic phage cocktail that targets PSC-derived Kp with a sustained suppressive effect in vitro. Oral administration of the phage cocktail lowers Kp levels in Kp-colonized germ-free mice and SPF mice, without off-target dysbiosis. Furthermore, we demonstrate that oral and intravenous phage administration successfully suppresses Kp levels and attenuates liver inflammation and disease severity in hepatobiliary injury-prone SPF mice. These results collectively suggest that using a lytic phage cocktail shows promise for targeting Kp in PSC.
Asunto(s)
Colangitis Esclerosante , Terapia de Fagos , Animales , Ratones , Colangitis Esclerosante/terapia , Klebsiella pneumoniae , Hígado/patología , Inflamación/patologíaRESUMEN
Host-microbe interactions orchestrate skin homeostasis, the dysregulation of which has been implicated in chronic inflammatory conditions such as atopic dermatitis and psoriasis. Here, we show that Staphylococcus cohnii is a skin commensal capable of beneficially inhibiting skin inflammation. We find that Tmem79-/- mice spontaneously develop interleukin-17 (IL-17)-producing T-cell-driven skin inflammation. Comparative skin microbiome analysis reveals that the disease activity index is negatively associated with S. cohnii. Inoculation with S. cohnii strains isolated from either mouse or human skin microbiota significantly prevents and ameliorates dermatitis in Tmem79-/- mice without affecting pathobiont burden. S. cohnii colonization is accompanied by activation of host glucocorticoid-related pathways and induction of anti-inflammatory genes in the skin and is therefore effective at suppressing inflammation in diverse pathobiont-independent dermatitis models, including chemically induced, type 17, and type 2 immune-driven models. As such, S. cohnii strains have great potential as effective live biotherapeutics for skin inflammation.
Asunto(s)
Inflamación/inmunología , Piel/patología , Staphylococcus/metabolismo , Animales , Humanos , RatonesRESUMEN
Acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Therefore, management of aGVHD is important for successful transplantation. Mucosal damage and alteration of the gut microbiota after allo-HSCT are key factors in the development of aGVHD. We conducted a prospective study to evaluate the ability of prebiotics, which can alleviate mucosal damage and manipulate the gut microbiota, to mitigate posttransplantation complications, including aGVHD. Resistant starch (RS) and a commercially available prebiotics mixture, GFO, were administered to allo-HSCT recipients from pretransplantation conditioning to day 28 after allo-HSCT. Prebiotic intake mitigated mucosal injury and reduced the incidence of all aGVHD grades combined and of aGVHD grades 2 to 4. The cumulative incidence of skin aGVHD was markedly decreased by prebiotics intake. Furthermore, the gut microbial diversity was well maintained and butyrate-producing bacterial population were preserved by prebiotics intake. In addition, the posttransplantation fecal butyrate concentration was maintained or increased more frequently in the prebiotics group. These observations indicate that prebiotic intake may be an effective strategy for preventing aGVHD in allo-HSCT, thereby improving treatment outcomes and the clinical utility of stem cell transplantation approaches. This study was registered on the University Hospital Medical Information Network (UMIN) clinical trials registry (https://www.umin.ac.jp/ctr/index.htm) as #UMIN000027563.
Asunto(s)
Microbioma Gastrointestinal , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Prebióticos , Estudios ProspectivosRESUMEN
Dysbiotic microbiota contributes to the pathogenesis of Crohn's disease (CD) by regulating the immune system. Although pro-inflammatory microbes are probably enriched in the small intestinal (SI) mucosa, most studies have focused on fecal microbiota. This study aimed to examine jejunal and ileal mucosal specimens from patients with CD via double-balloon enteroscopy. Comparative microbiome analysis revealed that the microbiota composition of CD SI mucosa differs from that of non-CD controls, with an increased population of several families, including Enterobacteriaceae, Ruminococcaceae, and Bacteroidaceae. Upon anaerobic culturing of the CD SI mucosa, 80 bacterial strains were isolated, from which 9 strains representing 9 distinct species (Escherichia coli, Ruminococcus gnavus, Klebsiella pneumoniae, Erysipelatoclostridium ramosum, Bacteroides dorei, B. fragilis, B. uniformis, Parabacteroides distasonis, and Streptococcus pasteurianus) were selected on the basis of their significant association with CD. The colonization of germ-free (GF) mice with the 9 strains enhanced the accumulation of TH1 cells and, to a lesser extent, TH17 cells in the intestine, among which an E. coli strain displayed high potential to induce TH1 cells and intestinal inflammation in a strain-specific manner. The present results indicate that the CD SI mucosa harbors unique pro-inflammatory microbiota, including TH1 cell-inducing E. coli, which could be a potential therapeutic target.
Asunto(s)
Enfermedad de Crohn/microbiología , Escherichia coli/patogenicidad , Mucosa Intestinal/microbiología , Intestino Delgado/microbiología , Células TH1/metabolismo , Adulto , Animales , Clostridiales/aislamiento & purificación , Clostridiales/patogenicidad , Enfermedad de Crohn/inmunología , Escherichia coli/aislamiento & purificación , Femenino , Microbioma Gastrointestinal , Humanos , Intestino Delgado/inmunología , Masculino , Ratones , Persona de Mediana Edad , Células Th17/metabolismoRESUMEN
There is a growing appreciation for the importance of the gut microbiota as a therapeutic target in various diseases. However, there are only a handful of known commensal strains that can potentially be used to manipulate host physiological functions. Here we isolate a consortium of 11 bacterial strains from healthy human donor faeces that is capable of robustly inducing interferon-γ-producing CD8 T cells in the intestine. These 11 strains act together to mediate the induction without causing inflammation in a manner that is dependent on CD103+ dendritic cells and major histocompatibility (MHC) class Ia molecules. Colonization of mice with the 11-strain mixture enhances both host resistance against Listeria monocytogenes infection and the therapeutic efficacy of immune checkpoint inhibitors in syngeneic tumour models. The 11 strains primarily represent rare, low-abundance components of the human microbiome, and thus have great potential as broadly effective biotherapeutics.
Asunto(s)
Adenocarcinoma/inmunología , Adenocarcinoma/terapia , Bacterias/clasificación , Linfocitos T CD8-positivos/inmunología , Microbioma Gastrointestinal/inmunología , Listeriosis/prevención & control , Simbiosis/inmunología , Adenocarcinoma/patología , Animales , Antígenos CD/metabolismo , Bacterias/inmunología , Bacterias/aislamiento & purificación , Linfocitos T CD8-positivos/citología , Línea Celular Tumoral , Células Dendríticas/inmunología , Heces/microbiología , Femenino , Voluntarios Sanos , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Cadenas alfa de Integrinas/metabolismo , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Listeriosis/microbiología , Masculino , Ratones , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Palladium(II) complexes with an auxiliary bidentate ligand featuring one C-Pd bond and a Pd-N-donor bond (palladacycles) have been shown to afford improved yields of homoallylic amines from a three-component coupling of boronic acids, allenes and imines in comparison to the yields of homoallylic amines achieved with the originally reported catalyst (Pd(OAc)2/P(t-Bu)3), thus extending the scope of the reaction. 31P NMR monitoring studies indicate that distinct intermediates featuring Pd-P bonds originate in the reactions catalyzed by either Pd(OAc)2/P(t-Bu)3 or the pallada(II)cycle/P(t-Bu)3 systems, suggesting that the role of the pallada(II)cycles is more complex than just precatalysts. The importance of an additional phosphine ligand in the reactions catalyzed the pallada(II)cycles was established, and its role in the catalytic cycle has been proposed. Insights into the nature of the reactive intermediates that limit the performance of the originally reported catalytic systems has been gained.
RESUMEN
To clarify the role of endogenous angiotensin (Ang)-converting enzyme 2 (ACE2) and its cleavage product, Ang 1-7, in the atherogenic stimulation of vascular cells, we investigated the effect of pharmacological inhibition of ACE2 and Mas, an Ang 1-7 receptor, on cellular responses against Ang II stimulation. We measured extracellular signal-regulated kinase (ERK) 1/2 phosphorylation by western blot, smooth muscle cell (SMC) proliferation by WST assay and the adhesion of monocytes labeled with PKH67 to endothelial cells (ECs) by fluorescence microplate reader. Cells were pretreated with Ang 1-7, olmesartan (Ang II type 1 receptor (AT1) blocker), DX600 (ACE2 inhibitor), -Ala7-Ang1-7 (D-Ala; Mas antagonist), or combinations of treatments before the application of Ang II. Treatment with Ang II increased phosphorylated ERK 1/2 of SMC and EC, proliferation of SMC and adhesion of monocyte to EC, which were blocked by olmesartan. Pretreatment with DX600 either did not accelerate or only slightly accelerated these cellular responses. However, when Ang II signaling through AT1 was reduced by olmesartan, the additional treatment with DX600 significantly blunted some of the effect of olmesartan. Similarly, pretreatment with D-Ala reduced the inhibitory effect of olmesartan in response to Ang II stimulation. Endogenous ACE2 in vascular cells may contribute to counteracting the Ang II-mediated cellular response partly by upregulating the Ang 1-7 signaling through Mas.
Asunto(s)
Angiotensina II/metabolismo , Angiotensina I/fisiología , Aterosclerosis/metabolismo , Músculo Liso Vascular/metabolismo , Miocitos del Músculo Liso/metabolismo , Fragmentos de Péptidos/fisiología , Peptidil-Dipeptidasa A/fisiología , Angiotensina I/metabolismo , Angiotensina II/análogos & derivados , Angiotensina II/farmacología , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Enzima Convertidora de Angiotensina 2 , Animales , Adhesión Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Inhibidores Enzimáticos/farmacología , Humanos , Imidazoles/farmacología , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Miocitos del Músculo Liso/efectos de los fármacos , Fragmentos de Péptidos/metabolismo , Fragmentos de Péptidos/farmacología , Péptidos/farmacología , Peptidil-Dipeptidasa A/metabolismo , Proto-Oncogenes Mas , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/fisiología , Ratas , Receptores Acoplados a Proteínas G/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/fisiología , Tetrazoles/farmacologíaRESUMEN
As angiotensin-converting enzyme-2 (ACE2) was identified as a negative regulator of the renin-angiotensin system, there have been many reports concerning its role in several tissues, including the kidney. However, the role of ACE2 during the development of diabetic nephropathy remains undetermined, as previous reports did not necessarily support a protective role against renal injury. Thus, we performed detailed observations of kidneys in ACE2-knockout (ACE2-KO) mice at early (4 weeks) and advanced (18 weeks) stages of diabetes. ACE2-KO and wild-type C57BL/6 mice were rendered diabetic by intraperitoneal injection of streptozotocin. Diabetic ACE2-KO mice showed earlier onset and more severe progression of albuminuria than those did wild-type mice. The elevation of serum creatinine and urea nitrogen levels at 18 weeks of diabetes was more prominent in ACE2-KO mice. Periodic acid-Schiff-stained cross-section of diabetic ACE2-KO mice showed a more severe time-dependent increase in glomerular/tubulointerstitial damage than did that of wild-type mice, confirmed by the immunostaining of alpha-smooth muscle actin, collagen IV and F4-80 antigen. Glomeruli of diabetic ACE2-KO mice showed earlier and more severe decrease in the expression of nephrin, whose degradation is involved in the onset of albuminuria, and more potent increase of vascular endothelial growth factor expression. In addition, treatment with AT1 receptor blocker olmesartan significantly, but not totally, ameliorated the functional and morphological deterioration of diabetic nephropathy in ACE2-KO mice. These results suggest that ACE2 might continuously protect from both glomerular and tubulointerstitial injury during the development of diabetic nephropathy. The renal-protective effect of ACE2 might involve more than just suppressing angiotensin II-mediated AT1 receptor signaling.
Asunto(s)
Diabetes Mellitus Experimental/enzimología , Nefropatías Diabéticas/enzimología , Nefronas/patología , Peptidil-Dipeptidasa A/metabolismo , Angiotensina II/sangre , Bloqueadores del Receptor Tipo 1 de Angiotensina II , Enzima Convertidora de Angiotensina 2 , Animales , Diabetes Mellitus Experimental/sangre , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Experimental/fisiopatología , Nefropatías Diabéticas/patología , Imidazoles , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Nefronas/metabolismo , Peptidil-Dipeptidasa A/genética , Fenotipo , Receptor de Angiotensina Tipo 1/metabolismo , TetrazolesRESUMEN
UNLABELLED: To investigate the role of macrophage inflammatory protein-1 beta (MIP-1beta) in the development of atherosclerosis, we designed an in vitro study to elucidate the mechanisms of monocyte-endothelium adhesion via intracellular reactive oxygen species (ROS). Angiotensin II (AngII) was used as a positive control. Furthermore, we examined the efficacy of MIP-1beta as a predictor of stroke and cardiovascular events in hypertensive patients. MIP-1beta or AngII stimulation significantly increased ROS production and adhesion of THP-1 cells to inflamed human umbilical vein endothelial cells. Cell adhesion and ROS production were inhibited in stimulated THP-1 cells by: inhibition of ROS signaling with N-acetylcysteine, diphenyleneiodonium, or PEG-Catalase; inhibition of PI3Kgamma with siRNA or LY294002; and by Rac1 siRNA. The MIP-1 beta or AngII stimulation did not increase surface expression of integrins, very late antigen 4 (VLA-4) and lymphocyte function-associated antigen 1 (LFA-1), but cell adhesion was reduced by using an antiVLA-4 or an antiLFA-1 antibody. Moreover, cell adhesion and ROS production stimulated with MIP-1beta or AngII were completely inhibited by fluvastatin. In our clinical study, patients with the highest quartile of MIP-1beta showed a higher risk of stroke and cardiovascular events by a Cox proportional-hazards model. In conclusion, MIP-1beta directly induced cell adhesion to endothelial cells through oxidative stress via PI3k-Rac1 cascades. Serum MIP-1beta level might be a useful predictor for cerebro-cardiovascular events in hypertensive patients. CONDENSED ABSTRACT: We designed an in vitro investigation to examine the role of MIP-1beta on the development of atherosclerosis, including cell adhesion involving CAMs and ROS production, compared with angiotensin II. Furthermore, we investigated the prognostic impact of MIP-1beta on stroke and cardiovascular events in hypertensive patients in a small cohort study.
Asunto(s)
Adhesión Celular/efectos de los fármacos , Quimiocina CCL4/farmacología , Especies Reactivas de Oxígeno/metabolismo , Acetilcisteína/farmacología , Análisis de Varianza , Western Blotting , Catalasa/farmacología , Línea Celular , Línea Celular Tumoral , Trastornos Cerebrovasculares/metabolismo , Quimiocina CCL4/metabolismo , Cromonas/farmacología , Inhibidores Enzimáticos/farmacología , Depuradores de Radicales Libres/farmacología , Humanos , Integrina alfa4beta1/metabolismo , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Modelos Biológicos , Morfolinas/farmacología , Compuestos Onio/farmacología , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Polietilenglicoles/farmacología , Interferencia de ARN , Proteína de Unión al GTP rac1/genética , Proteína de Unión al GTP rac1/metabolismoRESUMEN
Both strict blood pressure control and efferent artery dilatation are critical in reducing proteinuria, which in turn helps to regulate blood pressure. Benidipine, an L- and T-type calcium channel blocker, has the potential for increased effectiveness compared with L-type-dominant calcium channel blockers such as amlodipine. Therefore, we evaluated blood pressure and proteinuria after changeover from amlodipine to benidipine in poorly controlled hypertensive patients. Fifty-eight hypertensive outpatients undergoing amlodipine treatment and unable to achieve optimal blood pressure as determined by Japanese Society of Hypertension Guidelines for the Management of Hypertention (JSH 2004) were changed over to benidipine treatment. We measured blood pressure and pulse rate and assessed urinary protein excretion before and after changeover. Systolic and diastolic blood pressure dropped from 151/90 mmHg to 140/81 mmHg (p<0.0001). Mean blood pressure (p<0.0001) and pulse pressure (p=0.0069) were also reduced, but pulse rate increased from 75 bpm to 78 bpm (p=0.0047). Urinary protein excretion adjusted for urinary creatinine was reduced from 0.35 +/- 0.82 to 0.22 +/- 0.55 g/g creatinine (p=0.0119). The urinary protein reduction was observed only in patients with renin-angiotensin inhibition (p=0.0216). By switching from amlodipine to benidipine treatment, more than 80% of patients reduced their blood pressure, and more than 40% achieved optimal blood pressure. Higher urinary protein excretion (p<0.0001), lower glomerular filtration rate (p=0.0011) and presence of diabetes (p=0.0284) were correlated with reduction of urinary proteins during changeover. Taken together, our results suggest that benidipine may have greater efficacy than amlodipine in reducing blood pressure and proteinuria.
Asunto(s)
Amlodipino/uso terapéutico , Bloqueadores de los Canales de Calcio/uso terapéutico , Dihidropiridinas/uso terapéutico , Hipertensión/tratamiento farmacológico , Proteinuria/tratamiento farmacológico , Anciano , Amlodipino/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Dihidropiridinas/farmacología , Femenino , Adhesión a Directriz , Humanos , Riñón/efectos de los fármacos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Pulso Arterial , Sistema Renina-Angiotensina/efectos de los fármacosRESUMEN
BACKGROUND: Many experiments using young hypertensive animal models support the evidence that angiotensin-converting enzyme inhibitor or angiotensin receptor type 1 blocker attenuates the progression of cardiac hypertrophy. However, it is still unclear whether inhibiting the renin-angiotensin system can reverse age-related cardiac hypertrophy. To clarify the role of renin-angiotensin system inhibition in naturally advanced myocardial hypertrophy we treated spontaneously hypertensive, aging rats with an angiotensin-converting enzyme inhibitor or an angiotensin receptor type 1 blocker. METHODS: We used osmotic pumps to deliver the blood-pressure reducers temocaprilat, olmesartan, hydralazine, or saline for 4 weeks. RESULTS: Heart and body weights were significantly reduced in animals treated with temocaprilat or olmesartan compared with animals treated with hydralazine or saline. Histologic myocyte size and cardiac fibrosis were significantly attenuated by temocaprilat or olmesartan. Real-time polymerase chain reaction (PCR) revealed that temocaprilat or olmesartan suppressed expression of cardiac transforming growth factor-beta1 and fibroblast growth factor-2 mRNA, a marker of cardiac fibrosis. Cardiac and systemic oxidative stress assessed by 8-isoprostane levels was significantly reduced in animals treated with temocaprilat or olmesartan compared with hydralazine-treated or saline-treated rats. Renin-angiotensin system inhibition reduced cardiac expression of NAD(P)H oxidative components p22phox, p47phox, and gp91phox. CONCLUSIONS: Renin-angiotensin system inhibition can reverse age-related, advanced cardiac hypertrophy. The mechanism of reversal is partly due to suppression of cardiac oxidative stress.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Cardiomegalia/tratamiento farmacológico , Hipertensión/tratamiento farmacológico , Sistema Renina-Angiotensina/efectos de los fármacos , Envejecimiento/efectos de los fármacos , Bloqueadores del Receptor Tipo 1 de Angiotensina II/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Animales , Biomarcadores/metabolismo , Presión Sanguínea/efectos de los fármacos , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Fibrosis/tratamiento farmacológico , Masculino , Miocardio/metabolismo , NADPH Oxidasas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Endogámicas SHR , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Angiotensin receptor blockers (ARBs) are the recommended first-line antihypertensive treatment for managing chronic kidney disease, and strict blood pressure (BP) regulation is crucial for the reduction of proteinuria. Valsartan and candesartan are commonly used ARBs in Japan, with maximum permissible doses of 160 mg/day and 12 mg/day, respectively. We evaluated BP and proteinuria after changeover from the maximum dose of candesartan to the maximum dose of valsartan, in 55 poorly controlled hypertensive patients undergoing candesartan treatment who were unable to achieve optimal BP according to the Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2004). We measured BP and pulse rate and assessed urinary protein excretion (UPE) before and after changeover. Changeover was associated with decreases in systolic BP and diastolic BP from 158/89 mmHg to 150/86 mmHg (p<0.01). Changeover was also associated with a reduction in UPE adjusted to urinary creatinine from 0.35+/-0.19 g/g creatinine to 0.19+/-0.37 g/g creatinine (p=0.0271) in patients who had high urinary protein levels prior to changeover without significant decreases in BP (p=0.0184). According to multiple regression analysis, higher UPE (p<0.0001) and a lower glomerular filtration rate (GFR) (p=0.0011) prior to changeover were independently correlated with reduction in UPE. Our results suggest that the maximum dose of valsartan is more effective than the maximum dose of candesartan for reducing BP and proteinuria.
Asunto(s)
Bloqueadores del Receptor Tipo 1 de Angiotensina II/uso terapéutico , Antihipertensivos/uso terapéutico , Bencimidazoles/uso terapéutico , Hipertensión/tratamiento farmacológico , Riñón/fisiopatología , Tetrazoles/uso terapéutico , Valina/análogos & derivados , Anciano , Compuestos de Bifenilo , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Frecuencia Cardíaca/fisiología , Humanos , Hipertensión/fisiopatología , Riñón/efectos de los fármacos , Masculino , Persona de Mediana Edad , Proteinuria/fisiopatología , Valina/uso terapéutico , ValsartánRESUMEN
Angiotensin-converting enzyme 2 (ACE2) is a carboxypeptidase that cleaves angiotensin II to angiotensin 1-7. Recently, it was reported that mice lacking ACE2 (ACE2(-/y) mice) exhibited reduced cardiac contractility. Because mechanical pressure overload activates the cardiac renin-angiotensin system, we used ACE2(-/y) mice to analyze the role of ACE2 in the response to pressure overload. Twelve-week-old ACE2(-/y) mice and wild-type (WT) mice received transverse aortic constriction (TAC) or sham operation. Sham-operated ACE2(-/y) mice exhibited normal cardiac function and had morphologically normal hearts. In response to TAC, ACE2(-/y) mice developed cardiac hypertrophy and dilatation. Furthermore, their hearts displayed decreased cardiac contractility and increased fetal cardiac gene induction, compared with WT mice. In response to chronic pressure overload, ACE2(-/y) mice developed pulmonary congestion and increased incidence of cardiac death compared with WT mice. On a biochemical level, cardiac angiotensin II concentration and activity of mitogen-activated protein (MAP) kinases were markedly increased in ACE2(-/y) mice in response to TAC. Administration of candesartan, an AT1 subtype angiotensin receptor blocker, attenuated the hypertrophic response and suppressed the activation of MAP kinases in ACE2(-/y) mice. Activation of MAP kinases in response to angiotensin II was greater in cardiomyocytes isolated from ACE2(-/y) mice than in those isolated from WT mice. ACE2 plays an important role in dampening the hypertrophic response to pressure overload mediated by angiotensin II. Disruption of this regulatory function may accelerate cardiac hypertrophy and shorten the transition period from compensated hypertrophy to cardiac failure.
Asunto(s)
Angiotensina II/metabolismo , Carboxipeptidasas/genética , Eliminación de Gen , Corazón/fisiopatología , Hipertensión/fisiopatología , Miocardio/metabolismo , Angiotensina II/sangre , Angiotensina II/farmacología , Enzima Convertidora de Angiotensina 2 , Animales , Aorta , Carboxipeptidasas/metabolismo , Gasto Cardíaco Bajo/etiología , Gasto Cardíaco Bajo/genética , Cardiomegalia/etiología , Cardiomegalia/genética , Células Cultivadas , Constricción Patológica , Activación Enzimática/efectos de los fármacos , Expresión Génica , Hipertensión/genética , Masculino , Ratones , Ratones Noqueados , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Miocitos Cardíacos/enzimología , Concentración Osmolar , Peptidil-Dipeptidasa A , ARN Mensajero/metabolismoRESUMEN
To evaluate morning autonomic nervous activity and blood pressure profiles in hypertensive patients by analyzing heart rate variability and ambulatory blood pressure. Data from 82 patients with untreated essential hypertension were analyzed. We evaluated the 24-h profile of blood pressure and that of indices of autonomic nervous activity, i.e., the high frequency component (HF) and low frequency component/HF (LF/HF), which were obtained by wavelet transform of heart rate variability. Patients were classified by dipping status (nondippers, n=28; dippers, n=32; extreme-dippers, n=8; and risers, n=14) and morning blood pressure profile (large, n=9; small, n=60; and inverted, n=13). Nocturnal systolic blood pressure in extreme-dippers was significantly lower than that in the other groups; that in the risers was significantly higher (p<0.05). There were no significant group differences in daytime systolic blood pressure. Daytime and 24-h HF levels were significantly higher in the dipper vs. the riser group (p<0.05). Morning blood pressure elevation negatively correlated to preawake (p<0.01) and nocturnal blood pressure (p<0.05), but not to daytime and post-awake blood pressure. The preawake/postawake ratio of systolic blood pressure positively correlated to that of LF/HF (p<0.01) and negatively correlated to preawake HF levels (p<0.05). Multivariate regression analysis revealed that preawake HF levels (p=0.037) and preawake/postawake ratio of LF/HF (p=0.033) were independently correlated with morning blood pressure elevation ratio. Our results suggest that activation of HF before waking and LF/HF during waking might play an important role in the development of morning blood pressure elevation.
Asunto(s)
Sistema Nervioso Autónomo/fisiopatología , Monitoreo Ambulatorio de la Presión Arterial , Ritmo Circadiano , Frecuencia Cardíaca , Hipertensión/etiología , Adulto , Anciano , Anciano de 80 o más Años , Presión Sanguínea , Femenino , Humanos , Hipertensión/fisiopatología , Masculino , Persona de Mediana EdadRESUMEN
The goal of this study was to clarify the clinical usefulness and limitations of brachial-ankle pulse wave velocity (PWV) to evaluate hypertensive complications, in comparison with carotid-femoral PWV. Patients with essential hypertension (n=296, male/female=161/135; age=61.1+/-0.7 years) were enrolled. We measured brachial-ankle PWV, femoral-ankle PWV and carotid-femoral PWV simultaneously, and evaluated target organ damage and associated clinical conditions (cerebrovascular and cardiovascular disease) using the World Health Organization classification modified in 1999. Carotid-femoral PWV (p<0.0001; r=0.521) and brachial-ankle PWV (p<0.0001; r=0.478) but not femoral-ankle PWV were significantly correlated with age. Carotid-femoral PWV was significantly higher in patients with associated clinical conditions compared with that in patients with target organ damage (p<0.05) and those with no complications (p<0.0001). Brachial-ankle PWV was significantly higher in patients with associated clinical conditions (p<0.05) and target organ damage (p<0.05) compared to those with no complications, but there was no significant difference in brachial-ankle PWV between these two groups. Moreover, femoral-ankle PWV was significantly lower in patients with associated clinical conditions compared with that in patients with target organ damage (p<0.05). These data suggest that brachial-ankle PWV could underestimate arterial stiffness in hypertensive patients with a history of cardiovascular events.
Asunto(s)
Enfermedades Cardiovasculares/diagnóstico , Hipertensión/complicaciones , Pulso Arterial/métodos , Tobillo , Arteria Braquial/fisiopatología , Enfermedades Cardiovasculares/etiología , Arterias Carótidas/fisiopatología , Femenino , Arteria Femoral/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Curva ROCRESUMEN
Aggressive and optimal directional coronary atherectomy (DCA) using intravascular ultrasound (IVUS) guidance provides favorable outcomes within 1 year. However, no previous data are available on the changes that occur in target lesions for the long term after stand-alone DCA. This study's aim evaluates, using quantitative angiography and intravascular ultrasonography, the natural history of changes that occur in target lesions between short- (about 6 months) and long-term (>5 years) follow-up angiography after stand-alone DCA. Of 186 patients (221 lesions) with successful stand-alone DCA, 48 patients (53 lesions) underwent revascularization within 6 months, and 14 patients subsequently died, leaving a study population of 124 patients (154 lesions). Complete quantitative coronary angiography (QCA) was obtained in 91 patients (101 lesions) and complete serial IVUS assessment was obtained for 38 lesions before and after intervention and during follow-up. From short- to long-term follow-up angiography, the minimal luminal diameter significantly increased (from 2.12 to 2.56 mm; p <0.0001); lesion subgroups with >30% diameter stenosis at short-term follow-up angiography showed significant late regression as assessed by QCA. Serial IVUS assessment revealed that the vessel cross-sectional area did not change (from 17.3 to 17.4 mm(2); p = NS); however the lumen cross-sectional area significantly increased (from 7.3 to 9.5 mm(2); p <0.0001) due to the reduction of plaque plus media cross-sectional area (from 10.0 to 7.9 mm(2); p <0.0001). The change in lumen cross-sectional area correlated with the change in plaque plus media cross-sectional area (r = -0.686, p <0.0001). Target lesions show late regression due to plaque reduction at >5 years after stand-alone DCA.