RESUMEN
Cellular mechanisms that mediate steatohepatitis, an increasingly prevalent condition in the Western world for which no therapies are available, are poorly understood. Despite the fact that its synthetic agonists induce fatty liver, the liver X receptor (LXR) transcription factor remains a target of interest because of its anti-atherogenic, cholesterol removal, and anti-inflammatory activities. Here we show that tetratricopeptide repeat domain protein 39B (Ttc39b, C9orf52) (T39), a high-density lipoprotein gene discovered in human genome-wide association studies, promotes the ubiquitination and degradation of LXR. Chow-fed mice lacking T39 (T39(-/-)) display increased high-density lipoprotein cholesterol levels associated with increased enterocyte ATP-binding cassette transporter A1 (Abca1) expression and increased LXR protein without change in LXR messenger RNA. When challenged with a high fat/high cholesterol/bile salt diet, T39(-/-) mice or mice with hepatocyte-specific T39 deficiency show increased hepatic LXR protein and target gene expression, and unexpectedly protection from steatohepatitis and death. Mice fed a Western-type diet and lacking low-density lipoprotein receptor (Ldlr(-/-)T39(-/-)) show decreased fatty liver, increased high-density lipoprotein, decreased low-density lipoprotein, and reduced atherosclerosis. In addition to increasing hepatic Abcg5/8 expression and limiting dietary cholesterol absorption, T39 deficiency inhibits hepatic sterol regulatory element-binding protein 1 (SREBP-1, ADD1) processing. This is explained by an increase in microsomal phospholipids containing polyunsaturated fatty acids, linked to an LXRα-dependent increase in expression of enzymes mediating phosphatidylcholine biosynthesis and incorporation of polyunsaturated fatty acids into phospholipids. The preservation of endogenous LXR protein activates a beneficial profile of gene expression that promotes cholesterol removal and inhibits lipogenesis. T39 inhibition could be an effective strategy for reducing both steatohepatitis and atherosclerosis.
Asunto(s)
Aterosclerosis/genética , Hígado Graso/genética , Lipoproteínas HDL/deficiencia , Lipoproteínas HDL/genética , Receptores Nucleares Huérfanos/metabolismo , Transportador 1 de Casete de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5 , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8 , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Aterosclerosis/prevención & control , Aterosclerosis/terapia , Ácidos y Sales Biliares/metabolismo , Colesterol en la Dieta/metabolismo , HDL-Colesterol/metabolismo , Dieta Alta en Grasa , Ácidos Grasos Insaturados/metabolismo , Hígado Graso/prevención & control , Hígado Graso/terapia , Femenino , Regulación de la Expresión Génica , Hepatocitos/metabolismo , Ligandos , Lipogénesis/genética , Lipoproteínas/metabolismo , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Receptores X del Hígado , Masculino , Ratones , Receptores Nucleares Huérfanos/genética , Fosfatidilcolinas/biosíntesis , Fosfatidilcolinas/metabolismo , Estabilidad Proteica , Proteolisis , Receptores de LDL/deficiencia , Receptores de LDL/genética , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismo , UbiquitinaciónRESUMEN
OBJECTIVE: Reverse cholesterol transport (RCT) is a major mechanism by which HDL (high-density lipoprotein) protects against atherosclerosis. Endothelial lipase (EL) reportedly reduces HDL levels, which, in theory, would increase atherosclerosis. However, it remains unclear whether EL affects RCT in vivo. APPROACH AND RESULTS: Adenoviral vectors expressing EL or luciferase were intravenously injected into mice, and a macrophage RCT assay was performed. As expected, hepatic EL overexpression markedly reduced HDL levels. In parallel, plasma 3H-cholesterol counts from the EL-expressing mice decreased by 85% compared with control. Surprisingly, there was no difference in fecal 3H-cholesterol excretion between the groups. Kinetic studies revealed increased catabolism/hepatic uptake of 3HDL-cholesteryl ether, resulting in no change in fecal HDL-cholesteryl ester excretion in the mice. To explore underlying mechanisms for the preservation of RCT despite low HDL levels in the EL-expressing mice, we investigated the effects of hepatic SR-BI (scavenger receptor class B type I) knockdown. RCT assay revealed that knockdown of SR-BI alone reduced fecal excretion of macrophage-derived 3H-cholesterol. Interestingly, hepatic EL overexpression under SR-BI inhibition further attenuated fecal tracer counts as compared with control. Finally, we observed that EL overexpression enhanced in vivo RCT under pharmacological inhibition of hepatic ABCA1 (ATP-binding cassette transporter A1) by probucol. CONCLUSIONS: Hepatic EL expression compensates for reduced macrophage-derived cholesterol efflux to plasma because of low HDL levels by promoting cholesterol excretion to bile/feces via an SR-BI pathway, maintaining overall RCT in vivo. In contrast, EL-modified HDL might negatively regulate RCT via hepatic ABCA1. Despite extreme hypoalphalipoproteinemia, RCT is maintained in EL-expressing mice via SR-BI/ABCA1-dependent pathways.
Asunto(s)
Transportador 1 de Casete de Unión a ATP/metabolismo , HDL-Colesterol/sangre , Lipasa/biosíntesis , Hígado/enzimología , Macrófagos Peritoneales/metabolismo , Receptores Depuradores de Clase B/metabolismo , Adenoviridae/genética , Animales , Inducción Enzimática , Técnicas de Transferencia de Gen , Vectores Genéticos , Células Hep G2 , Humanos , Lipasa/genética , Ratones , Ratones Endogámicos C57BL , MicroARNs/genética , MicroARNs/metabolismo , Células RAW 264.7 , Interferencia de ARN , Receptores Depuradores de Clase B/genéticaRESUMEN
OBJECTIVE: Oxidized products of probucol, spiroquinone and diphenoquinone, were shown to increase cell cholesterol release and plasma high-density lipoprotein (HDL) by inhibiting degradation of ATP-binding cassette transporter A1. We investigated whether these compounds enhance reverse cholesterol transport in mice. APPROACH AND RESULTS: Spiroquinone and diphenoquinone increased ATP-binding cassette transporter A1 protein (2.8- and 2.6-fold, respectively, P<0.01) and apolipoprotein A-I-mediated cholesterol release (1.4- and 1.4-fold, P<0.01 and P<0.05, respectively) in RAW264.7 cells. However, diphenoquinone, but not spiroquinone, enhanced cholesterol efflux to HDL (+12%, P<0.05), whereas both increased ATP-binding cassette transporter G1 protein, by 1.8- and 1.6-fold, respectively. When given orally to mice, both compounds significantly increased plasma HDL-cholesterol, by 19% and 20%, respectively (P<0.05), accompanied by an increase in hepatic and macrophage ATP-binding cassette transporter A1 but not ATP-binding cassette transporter G1. We next evaluated in vivo reverse cholesterol transport by injecting RAW264.7 cells labeled with (3)H-cholesterol intraperitoneally into mice. Both spiroquinone and diphenoquinone increased fecal excretion of the macrophage-derived (3)H-tracer, by 25% and 28% (P<0.01 and P<0.05), respectively. spiroquinone/diphenoquinone did not affect fecal excretion of HDL-derived (3)H-cholesterol, implying that macrophage-to-plasma was the most important step in spiroquinone/diphenoquinone-mediated promotion of in vivo reverse cholesterol transport. Finally, spiroquinone significantly reduced aortic atherosclerosis in apolipoprotein E null mice when compared with the vehicle. CONCLUSIONS: Spiroquinone and diphenoquinone increase functional ATP-binding cassette transporter A1 in both the macrophages and the liver, elevate plasma HDL-cholesterol, and promote overall reverse cholesterol transport in vivo. These compounds are promising as therapeutic reagents against atherosclerosis.
Asunto(s)
Transportador 1 de Casete de Unión a ATP/efectos de los fármacos , Androstadienos/farmacología , Anticolesterolemiantes/farmacología , Aorta/efectos de los fármacos , Enfermedades de la Aorta/prevención & control , Aterosclerosis/prevención & control , Colesterol/sangre , Hipercolesterolemia/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Probucol/farmacología , Quinonas/farmacología , Transportador 1 de Casete de Unión a ATP/metabolismo , Animales , Aorta/metabolismo , Aorta/patología , Enfermedades de la Aorta/sangre , Enfermedades de la Aorta/genética , Enfermedades de la Aorta/patología , Apolipoproteína A-I/sangre , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/sangre , Aterosclerosis/genética , Aterosclerosis/patología , Transporte Biológico , HDL-Colesterol/sangre , Modelos Animales de Enfermedad , Heces/química , Hipercolesterolemia/sangre , Hipercolesterolemia/genética , Hígado/efectos de los fármacos , Hígado/metabolismo , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Oxidación-Reducción , Placa Aterosclerótica , Células RAW 264.7 , Factores de TiempoRESUMEN
Primary mural endocarditis is an extremely rare infection in which nonvalvular endocardial involvement is seen without any cardiac structural abnormalities such as ventricular septal defects. The rapid and precise diagnosis of this disease remains challenging. We present 2 cases (67- and 47-year-old male patients) of pathologically confirmed primary mural endocarditis that could have been detected by initial transthoracic echocardiography in the emergency department. Transthoracic echocardiography and transesophageal echocardiography play critical roles in the early recognition and confirmation of primary mural endocarditis.
Asunto(s)
Ecocardiografía Transesofágica , Endocarditis/diagnóstico , Endocarditis/terapia , Infecciones Estafilocócicas/diagnóstico , Infecciones Estafilocócicas/terapia , Anciano , Diagnóstico Diferencial , Endocarditis/diagnóstico por imagen , Resultado Fatal , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Reverse cholesterol transport (RCT) is pivotal in the return of excess cholesterol from peripheral tissues to the liver for excretion in bile and eventually feces. RCT from macrophages is a critical anti-atherogenicity mechanism of HDL. As the cholesterol absorption inhibitor ezetimibe promoted RCT in mice, which lack cholesterol ester transfer protein (CETP), we investigated its effects in hamsters, which have CETP. A high-cholesterol diet (HC) increased cholesterol levels throughout lipoprotein fractions and ezetimibe markedly reduced VLDL/LDL cholesterol levels under both normal chow (NC) and HC. However, ezetimibe did not affect and reduced HDL-cholesterol levels under NC and HC, respectively. Intraperitoneal injection of (3)H-cholesterol pre-labeled macrophages in an in vivo RCT assay increased tracer accumulation in the liver but reduced it in bile under HC, and these changes were completely cancelled by ezetimibe. Under both NC and HC, ezetimibe reduced tracer levels in the liver but increased them in feces, indicating promotion of RCT in vivo. We performed a RCT assay using hamsters subjected to bile duct ligation (BDL) to clarify whether a transintestinal cholesterol efflux (TICE) pathway contributes to ezetimibe's enhancement of RCT. BDL markedly inhibited macrophage-derived (3)H-cholesterol excretion to feces and cancelled ezetimibe's stimulatory effect on RCT, suggesting that biliary cholesterol excretion is a major contributor in RCT promotion by ezetimibe but the contribution of the TICE pathway is minimal. In conclusions, ezetimibe exerts an additive anti-atherogenic property by enhancing RCT in hamsters. Our findings suggest that this property is independent of the TICE pathway.
Asunto(s)
Anticolesterolemiantes/farmacología , Azetidinas/farmacología , Bilis/efectos de los fármacos , HDL-Colesterol/metabolismo , Hígado/efectos de los fármacos , Macrófagos/efectos de los fármacos , Animales , Bilis/metabolismo , Conductos Biliares/cirugía , Transporte Biológico/efectos de los fármacos , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , LDL-Colesterol/metabolismo , VLDL-Colesterol/metabolismo , Cricetinae , Dieta , Ezetimiba , Heces/química , Hígado/metabolismo , Macrófagos/citología , Macrófagos/metabolismo , Masculino , TritioRESUMEN
OBJECTIVE: Low-density lipoprotein receptor (LDLR) is degraded by inducible degrader of LDLR (Idol) and protein convertase subtilisin/kexin type 9 (PCSK9), thereby regulating circulating LDL levels. However, it remains unclear whether, and if so how, these LDLR degraders affect each other. We therefore investigated effects of liver-specific expression of Idol on LDL/PCSK9 metabolism in mice and hamsters. APPROACH AND RESULTS: Injection of adenoviral vector expressing Idol (Ad-Idol) induced a liver-specific reduction in LDLR expression which, in turn, increased very-low-density lipoprotein/LDL cholesterol levels in wild-type mice because of delayed LDL catabolism. Interestingly, hepatic Idol overexpression markedly increased plasma PCSK9 levels. In LDLR-deficient mice, plasma PCSK9 levels were already elevated at baseline and unchanged by Idol overexpression, which was comparable with the observation for Ad-Idol-injected wild-type mice, indicating that Idol-induced PCSK9 elevation depended on LDLR. In wild-type mice, but not in LDLR-deficient mice, Ad-Idol enhanced hepatic PCSK9 expression, with activation of sterol regulatory element-binding protein 2 and subsequently increased expression of its target genes. Supporting in vivo findings, Idol transactivated PCSK9/LDLR in sterol regulatory element-binding protein 2/LDLR-dependent manners in vitro. Furthermore, an in vivo kinetic study using (125)I-labeled PCSK9 revealed delayed clearance of circulating PCSK9, which could be another mechanism. Finally, to extend these findings into cholesteryl ester transfer protein-expressing animals, we repeated the above in vivo experiments in hamsters and obtained similar results. CONCLUSIONS: A vicious cycle in LDLR degradation might be generated by PCSK9 induced by hepatic Idol overexpression via dual mechanisms: sterol regulatory element-binding protein 2/LDLR. Furthermore, these effects would be independent of cholesteryl ester transfer protein expression.
Asunto(s)
Hígado/metabolismo , Proproteína Convertasas/sangre , Receptores de LDL/fisiología , Serina Endopeptidasas/sangre , Transducción de Señal , Proteína 2 de Unión a Elementos Reguladores de Esteroles/fisiología , Ubiquitina-Proteína Ligasas/fisiología , Animales , Proteínas de Transferencia de Ésteres de Colesterol/fisiología , Cricetinae , Células Hep G2 , Humanos , Lipoproteínas LDL/metabolismo , Receptores X del Hígado , Mesocricetus , Ratones , Ratones Endogámicos C57BL , Receptores Nucleares Huérfanos/fisiología , Proproteína Convertasa 9 , Proproteína Convertasas/fisiología , Serina Endopeptidasas/fisiologíaRESUMEN
Stearoyl-coenzyme A desaturase 1 (SCD1) is the rate-limiting enzyme in the synthesis of monounsaturated fatty acids. However, the impact of SCD1 on atherosclerosis remains unclear. The aim of this study was to determine whether SCD1 affects macrophage reverse cholesterol transport (RCT) in mice. Compared to the control, adenoviral-mediated SCD1 overexpression in RAW264.7 macrophages increased cholesterol efflux to HDL, but not to apoA-I, without clear changes in ABCA1, ABCG1 and SR-BI expressions. While knockdown of ABCG1 and SR-BI did not affect the SCD1-induced cholesterol efflux to HDL, SCD1-overexpressing macrophages promoted the formation of both normal- and large-sized HDL in media, accompanying increased apolipoprotein A-I levels in HDL fractions. Transformation to larger particles of HDL was independently confirmed by nuclear magnetic resonance-based lipoprotein analysis. Interestingly, media transfer assays revealed that HDL generated by SCD1 had enhanced cholesterol efflux potential, indicating that SCD1 transformed HDL to a more anti-atherogenic phenotype. To study macrophage RCT in vivo, (3)H-cholesterol-labeled RAW264.7 cells overexpressing SCD1 or the control were intraperitoneally injected into mice. Supporting the in vitro data, injection of SCD1-macrophages resulted in significant increases in (3)H-tracer in plasma, liver, and feces compared to the control. Moreover, there was a shift towards larger particles in the (3)H-tracer distribution of HDL fractions obtained from the mice. In conclusion, macrophage-specific SCD1 overexpression promotes overall RCT through increased cholesterol efflux to HDL, suggesting that macrophage SCD1 achieves an anti-atherogenic effect by enhancing RCT.
Asunto(s)
Colesterol/metabolismo , Regulación Enzimológica de la Expresión Génica , Lipoproteínas HDL/metabolismo , Macrófagos/enzimología , Estearoil-CoA Desaturasa/biosíntesis , Transportador 1 de Casete de Unión a ATP , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1 , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Animales , Aterosclerosis/enzimología , Aterosclerosis/genética , Aterosclerosis/patología , Aterosclerosis/terapia , Transporte Biológico Activo/genética , Línea Celular , Colesterol/genética , Humanos , Lipoproteínas/genética , Lipoproteínas/metabolismo , Lipoproteínas HDL/genética , Macrófagos/patología , Ratones , Estearoil-CoA Desaturasa/genéticaRESUMEN
Reverse cholesterol transport (RCT) is a mechanism critical to the anti-atherogenic property of HDL. Although citrulline contributes to the amelioration of atherosclerosis via endothelial nitric oxide production, it remains unclear whether it affects RCT. This study was undertaken to clarify the effects of citrulline on expressions of specific transporters such as ATP binding cassette transporters (ABC)A1 and ABCG1, and the cholesterol efflux from macrophages to apolipoprotein (apo) A-I or HDL in vitro and ex vivo. Citrulline increased ABCA1 and ABCG1 mRNA and protein levels in THP-1 macrophages, translating into enhanced apoA-I- and HDL-mediated cholesterol efflux. In the human crossover study, 8 healthy male volunteers (age 30-49 years) consumed either 3.2 g/day citrulline or placebo for 1 week. Citrulline consumption brought about significant increases in plasma levels of citrulline and arginine. Supporting the in vitro data, monocyte-derived macrophages (MDM) differentiated under autologous post-citrulline sera demonstrated enhancement of both apoA-I- and HDL-mediated cholesterol efflux through increased ABCA1 and ABCG1 expressions, compared to MDM differentiated under pre-citrulline sera. However, the placebo did not modulate these parameters. Therefore, in addition to improving endothelium function, citrulline might have an anti-atherogenic property by increasing RCT of HDL.
RESUMEN
ABC transporter G1 (ABCG1) plays a pivotal role in HDL-mediated cholesterol efflux and atherogenesis. We investigated whether, and how, retinoic acid receptors (RARs) regulate ABCG1 expression in macrophages. All-trans retinoic acid (ATRA), an RAR ligand, increased ABCG1 protein levels and apoA-I/HDL-mediated cholesterol efflux from the macrophages. Both ATRA and other RAR agonists, TTNPB and Am580, increased major transcripts driven by promoter B upstream of exon 5, though minor transcripts driven by promoter A upstream of exon 1 were only increased by ATRA. The stimulatory effects of ATRA on ABCG1 expression were completely abolished in the presence of RAR/RXR antagonists but were only partially canceled in the presence of an LXR antagonist. Adenovirus with overexpressed oxysterol sulfotransferase abolished the LXR pathway, as previously reported, and ATRA-responsiveness in ABCA1/ABCG1 expressions were respectively attenuated by 38 and 22% compared to the control virus. Promoter assays revealed that ABCG1 levels were regulated more by promoter B than promoter A, and ATRA activated promoter B in a liver X receptor-responsive element (LXRE)-dependent manner. Further, LXRE-B in intron 7, but not LXRE-A in intron 5, enhanced ATRA responsiveness under overexpression of all RAR isoforms-RARα/ß/γ. In contrast, the activation of promoter B by TTNPB depended on LXRE-B and RARα, but not on RARß/γ. Finally, chromatin immunoprecipitation and gel-shift assays revealed a specific and direct repeat 4-dependent binding of RARα to LXRE-B. In conclusion, RAR ligands increase ABCA1/G1 expression and apoA-I/HDL-mediated cholesterol efflux from macrophages, and modulate ABCG1 promoter activity via LXRE-dependent mechanisms.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/metabolismo , Macrófagos/efectos de los fármacos , Receptores de Ácido Retinoico/agonistas , Tretinoina/farmacología , Transportador 1 de Casete de Unión a ATP , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1 , Transportadoras de Casetes de Unión a ATP/genética , Animales , Benzoatos/farmacología , Transporte Biológico/efectos de los fármacos , Western Blotting , Células COS , Línea Celular , Chlorocebus aethiops , Colesterol/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Células HEK293 , Humanos , Receptores X del Hígado , Macrófagos/citología , Macrófagos/metabolismo , Modelos Genéticos , Receptores Nucleares Huérfanos/agonistas , Receptores Nucleares Huérfanos/genética , Receptores Nucleares Huérfanos/metabolismo , Regiones Promotoras Genéticas/genética , Unión Proteica/efectos de los fármacos , Receptores de Ácido Retinoico/genética , Receptores de Ácido Retinoico/metabolismo , Elementos de Respuesta/genética , Receptores X Retinoide/agonistas , Receptores X Retinoide/genética , Receptores X Retinoide/metabolismo , Retinoides/farmacología , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal/efectos de los fármacos , Tetrahidronaftalenos/farmacologíaRESUMEN
Endothelium-bound extracellular superoxide dismutase (eEC-SOD), a major antioxidative enzyme in the vasculature, is involved in anti-atherogenesis by inhibiting low-density lipoprotein (LDL) oxidation. The objective was to investigate whether the polyphenol-rich juar tea had beneficial effects on LDL oxidation and eEC-SOD levels in patients with metabolic syndrome (MetS). A total of 20 men with MetS participated in a randomized cross-over trial, comparing consumption of five cups/day of juar tea with that of a polyphenol-poor tea, barley tea, for 4 weeks. Although there was no change in LDL oxidizability after consumption of either tea, juar tea significantly increased eEC-SOD levels by 16% (p < 0.05), whereas barley tea significantly decreased levels by 15% (p < 0.05). It is noteworthy that the changes in eEC-SOD were positively associated with those in LDL oxidizability after tea consumption (r(2) = 0.11, p < 0.05). Tea polyphenols may provide anti-atherosclerotic effects by inhibiting LDL oxidation through EC-SOD bound to the endothelium.
Asunto(s)
Camellia sinensis/química , Endotelio Vascular/efectos de los fármacos , Lipoproteínas LDL/metabolismo , Síndrome Metabólico/tratamiento farmacológico , Fitoterapia , Polifenoles/uso terapéutico , Superóxido Dismutasa/metabolismo , Adulto , Antioxidantes/metabolismo , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Aterosclerosis/metabolismo , Aterosclerosis/prevención & control , Endotelio Vascular/metabolismo , Hordeum , Humanos , Masculino , Síndrome Metabólico/metabolismo , Oxidación-Reducción , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Polifenoles/farmacología , Té/químicaRESUMEN
To assess temporal changes to the risk of death in COVID-19 cases caused by the Omicron variant, we calculated age-standardized case fatality rates (CFR) in patients aged ≥40 years over nine diagnostic periods (3 January to 28 August 2022) in ten Japanese prefectures (14.8 million residents). Among 552,581 study subjects, we found that there were 1836 fatalities during the isolation period (up to 28 days from date of onset). The highest age-standardized CFR (0.85%, 95% confidence interval (CI):0.78-0.92) was observed in cases diagnosed in the second 4-week period (January 31 to February 27), after which it declined significantly up to the 6th 4-week period (0.23%, 95% CI: 0.13-0.33, May 23 to June 19). The CFR then increased again but remained at 0.39% in the eighth period (July 18 to August 28). The CFR in cases with the BA.2 or BA.5 sublineages in the age range 60-80 years was significantly lower than that with BA.1 infections (60 years: 0.19%, 0.02%, 0.053%, respectively; 70 years: 0.91%, 0.33%, 0.39%; ≥80 years: 3.78%, 1.96%, 1.81%, respectively). We conclude that the risk of death in Japanese COVID-19 patients infected with Omicron variants declined through February to mid-June 2022.
Asunto(s)
COVID-19 , Pueblos del Este de Asia , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , COVID-19/mortalidad , COVID-19/virología , Prevalencia , SARS-CoV-2RESUMEN
RATIONALE: Association of habitual coffee consumption with coronary heart disease morbidity and mortality has not been established. We hypothesized that coffee may enhance reverse cholesterol transport (RCT) as the antiatherogenic properties of high-density lipoprotein (HDL). OBJECTIVE: This study was to investigate whether the phenolic acids of coffee and coffee regulates RCT from macrophages in vitro, ex vivo and in vivo. METHODS AND RESULTS: Caffeic acid and ferulic acid, the major phenolic acids of coffee, enhanced cholesterol efflux from THP-1 macrophages mediated by HDL, but not apoA-I. Furthermore, these phenolic acids increased both the mRNA and protein levels of ATP-binding cassette transporter (ABC)G1 and scavenger receptor class B type I (SR-BI), but not ABCA1. Eight healthy volunteers were recruited for the ex vivo study, and blood samples were taken before and 30 minutes after consumption of coffee or water in a crossover study. The mRNA as well as protein levels of ABCG1, SR-BI, and cholesterol efflux by HDL were increased in the macrophages differentiated under autologous sera obtained after coffee consumption compared to baseline sera. Finally, effects of coffee and phenolic acid on in vivo RCT were assessed by intraperitoneally injecting [(3)H]cholesterol-labeled acetyl low-density lipoprotein-loaded RAW264.7 cells into mice, then monitoring appearance of (3)H tracer in plasma, liver, and feces. Supporting in vitro and ex vivo data, ferulic acid was found to significantly increase the levels of (3)H tracer in feces. CONCLUSIONS: Coffee intake might have an antiatherogenic property by increasing ABCG1 and SR-BI expression and enhancing HDL-mediated cholesterol efflux from the macrophages via its plasma phenolic acids.
Asunto(s)
Bebidas , Ácidos Cafeicos/farmacología , Colesterol/metabolismo , Café , Ácidos Cumáricos/farmacología , Lipoproteínas HDL/metabolismo , Macrófagos/efectos de los fármacos , Transportador 1 de Casete de Unión a ATP , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1 , Transportadoras de Casetes de Unión a ATP/genética , Transportadoras de Casetes de Unión a ATP/metabolismo , Adulto , Animales , Apolipoproteína A-I/metabolismo , Bilis/metabolismo , Transporte Biológico , Ácidos Cafeicos/sangre , Línea Celular , Colesterol/sangre , Enfermedad Coronaria/metabolismo , Enfermedad Coronaria/prevención & control , Ácidos Cumáricos/sangre , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Heces/química , Femenino , Genes Reporteros , Humanos , Lipoproteínas HDL/sangre , Lipoproteínas LDL/metabolismo , Hígado/metabolismo , Macrófagos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , ARN Mensajero/metabolismo , Receptores Depuradores de Clase B/genética , Receptores Depuradores de Clase B/metabolismo , Factores de Tiempo , Transfección , Regulación hacia ArribaRESUMEN
OBJECTIVE: ATP-binding cassette transporter A1 (ABCA1) and ABCG1 are key molecules in an initial step of reverse cholesterol transport (RCT), a major antiatherogenic property of high-density lipoprotein (HDL). The ubiquitin-proteasome system (UPS) mediates nonlysosomal pathways for protein degradation and is known to be involved in atherosclerosis. However, little is known about the effects of the UPS on these molecules and overall RCT. We therefore investigated whether UPS inhibition affects ABCA1/G1 expression in macrophages and RCT in vitro and in vivo. METHODS AND RESULTS: Various proteasome inhibitors increased ABCA1/G1 expression in macrophages, translating into enhanced apolipoprotein A-I- and HDL-mediated cholesterol efflux from macrophages. ABCA1 and ABCG1 were found to undergo polyubiquitination in the macrophages and HEK293 cells overexpressing these proteins, and pulse-chase analysis revealed that proteasome inhibitors inhibited ABCA1/G1 protein degradation. In in vivo experiments, the proteasome inhibitor bortezomib increased ABCA1/G1 protein levels in mouse peritoneal macrophages, and RCT assays showed that it significantly increased the fecal (54% increase compared with saline) and plasma (23%) appearances of the tracer derived from intraperitoneally injected (3)H-cholesterol-labeled macrophages. CONCLUSIONS: The present study provided evidence that the UPS is involved in ABCA1/G1 degradation, thereby affecting RCT in vivo. Therefore, specific inhibition of the UPS pathway might lead to a novel HDL therapy that enhances RCT.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/fisiología , Colesterol/metabolismo , Lipoproteínas/fisiología , Macrófagos/metabolismo , Complejo de la Endopetidasa Proteasomal/fisiología , Transportador 1 de Casete de Unión a ATP , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 1 , Transportadoras de Casetes de Unión a ATP/análisis , Animales , Apolipoproteína A-I/fisiología , Ácidos Borónicos/farmacología , Bortezomib , Células Cultivadas , Células Hep G2 , Humanos , Lipoproteínas/análisis , Lipoproteínas HDL/fisiología , Ratones , Fosforilación , Inhibidores de Proteasoma , Pirazinas/farmacología , Ubiquitina-Proteína Ligasas/fisiología , UbiquitinaciónRESUMEN
AIMS: Inflammation is involved in various processes of atherosclerosis development. Serum C-reactive protein (CRP) levels, a predictor for cardiovascular risk, are reportedly reduced by statins. However, several studies have demonstrated that CRP is a bystander during atherogenesis. While S100A12 has been focused on as an inflammatory molecule, it remains unclear whether statins affect circulating S100A12 levels. Here, we investigated whether atorvastatin treatment affected S100A12 and which biomarkers were correlated with changes in arterial inflammation. METHODS: We performed a prospective, randomized open-labeled trial on whether atorvastatin affected arterial (carotid and thoracic aorta) inflammation using 18fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) and inflammatory markers. Thirty-one statin-naïve patients with carotid atherosclerotic plaques were randomized to either a group receiving dietary management (n=15) or one receiving atorvastatin (10mg/day, n=16) for 12weeks. 18F-FDG-PET/CT and flow-mediated vasodilation (FMD) were performed, the latter to evaluate endothelial function. RESULTS: Atorvastatin, but not the diet-only treatment, significantly reduced LDL-cholesterol (LDL-C, -43%), serum CRP (-37%) and S100A12 levels (-28%) and improved FMD (+38%). 18F-FDG-PET/CT demonstrated that atorvastatin, but not the diet-only treatment, significantly reduced accumulation of 18F-FDG in the carotid artery and thoracic aorta. A multivariate analysis revealed that reduction in CRP, S100A12, LDL-C, oxidized-LDL, and increase in FMD were significantly associated with reduced arterial inflammation in the thoracic aorta, but not in the carotid artery. CONCLUSIONS: Atorvastatin treatment reduced S100A12/CRP levels, and the changes in these circulating markers mirrored the improvement in arterial inflammation. Our observations suggest that S100A12 may be an emerging therapeutic target for atherosclerosis.
Asunto(s)
Arteritis , Aterosclerosis , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Placa Aterosclerótica , Aterosclerosis/metabolismo , Atorvastatina/uso terapéutico , Biomarcadores , Arterias Carótidas/diagnóstico por imagen , Arterias Carótidas/metabolismo , LDL-Colesterol/metabolismo , Fluorodesoxiglucosa F18 , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Inflamación/tratamiento farmacológico , Placa Aterosclerótica/tratamiento farmacológico , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Estudios Prospectivos , Proteína S100A12RESUMEN
AIMS: In contemporary heart failure (HF) practice, prognostic value for combinations of cardiac and non-cardiac predictors remains poorly understood. We analysed the combinatorial predictors of outcomes in acute HF patients. METHODS AND RESULTS: This longitudinal cohort study included consecutive patients admitted for acute decompensated HF between April 2015 and March 2018 in an urban hospital. The main outcomes are HF readmission within 6 months after discharge or all-cause death. A total of 451 patients with 662 admissions were enrolled and the data including frailty and echocardiographic parameters were analysed by multivariate and matched cohort analyses. The mean age of the patients was 76.8 years. We constructed a multi-frailty index (MFI) ranging from 0 to 3 points as a composite of non-cardiac comorbidities and biopsychosocial frailty. In matched cohort of patients with ejection fraction â§50% (HFpEF), MFI â§1, pulmonary hypertension (PH; peak flow velocity of tricuspid regurgitation â§2.9 m/s by echocardiography), and pancytopenia at discharge were strong predictors of HF readmission [odds ratios (ORs), 4.33, 2.5, and 2.86; P = 0.02, 0.05, and 0.02, respectively], and MFI â§2 was the only predictor for all-cause death. For ejection fraction <40%, age, BNP â§800 pg/mL, increase in estimated glomerular filtration rate during hospitalization, and lymphocytopenia plus anaemia predicted HF readmission (ORs, 1.77, 2.72, 0.73, and 2.89; P = 0.001, 0.05, 0.04, and 0.03, respectively). In contrast, diabetes mellitus was the only specific predictor found in patients over 80 years old. CONCLUSION: These data identified multi-frailty and PH or mild pancytopenia as synergistic predictors of HF readmission in HFpEF patients.
Asunto(s)
Insuficiencia Cardíaca , Anciano , Anciano de 80 o más Años , Ecocardiografía , Insuficiencia Cardíaca/epidemiología , Humanos , Estudios Longitudinales , Pronóstico , Volumen SistólicoRESUMEN
BACKGROUND: Low-dose aspirin is used for secondary prevention of ischemic heart disease and ischemic cerebrovascular disease. Currently, the frequency of gastrointestinal disorder among users of low-dose aspirin is unknown. AIMS: To investigate through endoscopic examination the frequency of gastroduodenal disorder associated with buffered and enteric-coated aspirin (ECA). METHODS: Screening upper endoscopic examinations were prospectively performed on 236 patients with ischemic heart disease. Endoscopic findings including ulcers and flat erosions were assessed as mucosal defects. RESULTS: Mucosal defects were found in 92 of 190 (48.4%) users of low-dose aspirin and 6 of 46 (13.0%) nonusers. There were significantly more mucosal defects among users of low-dose aspirin than among those using no aspirin (P<0.0001). Mucosal defects were found in 54 of 98 (60.7%) users of buffered aspirin (BA), whereas 38 of 101 (37.6%) users of ECA had mucosal defects. Users of ECA had significantly fewer erosions than did those of BA (P=0.0015). The frequency of ulcer is similar between BA users and ECA users. CONCLUSIONS: As endoscopy frequently reveals gastroduodenal disorder among low-dose aspirin users, both administration of BA and of enteric-coated aspirin warrant concern for gastroduodenal ulcer.
Asunto(s)
Antiinflamatorios no Esteroideos/efectos adversos , Aspirina/efectos adversos , Duodeno , Mucosa Gástrica , Mucosa Intestinal , Isquemia Miocárdica/tratamiento farmacológico , Anciano , Antiinflamatorios no Esteroideos/administración & dosificación , Aspirina/administración & dosificación , Tampones (Química) , Esquema de Medicación , Duodeno/efectos de los fármacos , Duodeno/patología , Endoscopía Gastrointestinal , Femenino , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/patología , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Gastrointestinales/patología , Humanos , Mucosa Intestinal/efectos de los fármacos , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Comprimidos RecubiertosRESUMEN
BACKGROUND AND AIM: Low-dose aspirin is effective for the prevention of cardiovascular and cerebrovascular events, but the frequency of gastrointestinal injuries among users of low-dose aspirin in Japan is currently unknown. In the present study endoscopic examination was performed to investigate the frequency of gastroduodenal injuries associated with low-dose aspirin in patients with ischemic heart disease (IHD). METHODS: Screening upper endoscopic examinations were prospectively performed on 131 patients with IHD who were not receiving antiulcer treatment. Endoscopic findings such as ulcers and flat erosions were assessed as mucosal injuries. RESULTS: Mucosal injuries were found in 62 of 101 (61.4%) low-dose aspirin users and three of 30 (10%) nonaspirin users. There were significantly more mucosal injuries among low-dose aspirin users than among the non-users (P<0.0001). Gastroduodenal ulcers were found in 19 of 101 (18.8%) low-dose aspirin users compared with one of 30 (3.3%) nonaspirin users. The frequency of mucosal injuries was not associated with the duration of aspirin treatment. CONCLUSION: Endoscopy frequently reveals low-dose aspirin-induced gastroduodenal injuries in patients with IHD.
Asunto(s)
Aspirina/efectos adversos , Úlcera Duodenal/inducido químicamente , Duodenoscopía , Mucosa Gástrica/efectos de los fármacos , Gastroscopía , Mucosa Intestinal/efectos de los fármacos , Isquemia Miocárdica/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/efectos adversos , Úlcera Gástrica/inducido químicamente , Anciano , Aspirina/administración & dosificación , Estudios de Casos y Controles , Esquema de Medicación , Úlcera Duodenal/patología , Femenino , Mucosa Gástrica/patología , Humanos , Mucosa Intestinal/patología , Masculino , Persona de Mediana Edad , Inhibidores de Agregación Plaquetaria/administración & dosificación , Estudios Prospectivos , Úlcera Gástrica/patologíaRESUMEN
A 25-year-old previously healthy man was hospitalized for syncope. While standing, he suddenly lost consciousness, followed by a generalized tonic clonic seizure. An electrocardiogram demonstrated asystole. No cardiac abnormalities were detected on the echocardiogram, cardiac magnetic resonance imaging (MRI), positron emission tomography, or a coronary angiogram. An electrophysiological study showed normal sinus node and atrioventricular node function. An electroencephalogram revealed small spike waves in the fronto-temporal region. Brain MRI demonstrated a left-sided amygdala enlargement. To the best of our knowledge, this is the first case of temporal lobe epilepsy with an amygdala enlargement that induced cardiac asystole.