RESUMEN

Epidemiological studies have shown an association between type 2 diabetes (T2D) and calcific aortic valve stenosis (CAVS), but the potential causal relationship and underlying mechanisms remain unclear. Therefore, we conducted a two-sample and two-step Mendelian randomization (MR) analysis to evaluate the association of T2D with CAVS and the mediating effects of circulating metabolites and blood pressure using genome-wide association study (GWAS) summary statistics. The inverse variance weighted (IVW) method was used for the primary MR analysis, and comprehensive sensitivity analyses were performed to validate the robustness of the results. Our results showed that genetically predicted T2D was associated with increased CAVS risk (OR 1.153, 95% CI 1.096-1.214, p < 0.001), and this association persisted even after adjusting for adiposity traits in multivariable MR analysis. Furthermore, the two-step MR analysis identified 69 of 251 candidate mediators that partially mediated the effect of T2D on CAVS, including total branched-chain amino acids (proportion mediated: 23.29%), valine (17.78%), tyrosine (9.68%), systolic blood pressure (8.72%), the triglyceride group (6.07-11.99%), the fatty acid group (4.78-12.82%), and the cholesterol group (3.64-11.56%). This MR study elucidated the causal impact of T2D on CAVS risk independently of adiposity and identified potential mediators in this association pathways. Our findings shed light on the pathogenesis of CAVS and suggest additional targets for the prevention and intervention of CAVS attributed to T2D.

RESUMEN

Hippo pathway plays a crucial role as a regulator of organ size and tumorigenesis that negatively regulates cell growth and survival. Recently lots of evidences show that Hippo pathway plays a crucial role in glucose metabolic metabolism to regulate energy status with cell growth. However, the detailed mechanism is still unclear. Here we report that Yes-associated protein (YAP), the terminal effector of Hippo pathway, interacts with carbohydrate response element binding protein (ChREBP) in the nucleus of the hepatocytes thereby promoting glycolysis and lipogenesis. A high carbohydrate (HCHO) diet could inactivate the Hippo pathway and encourage the combination of YAP and ChREBP, leading to glucose-induced hepatocyte glycolysis and lipogenesis through up-regulation of target genes such as L-PK and ACC in mice. Conversely, inhibition of YAP activity by phosphorylation or downregulation antagonized glycolysis and lipogenesis in mice fed with HCHO diet. These results suggest that YAP is a nuclear co-factor of ChREBP and that the Hippo pathway negatively affects hepatocyte glycolysis by inhibiting the function of YAP-ChREBP.

Asunto(s)

Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Glucosa/metabolismo , Hígado/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Transducción de Señal , Animales , Glucólisis , Vía de Señalización Hippo , Lipogénesis , Masculino , Ratones Endogámicos C57BL

RESUMEN

We report a case of rotational-atherectomy induced fistula between the diagonal branch and the accompanying vein. Thus far, the patient has had no relevant symptoms; thus, no intervention has been undertaken. We will closely monitor the patient to determine future treatment.

Asunto(s)

Fístula Arteriovenosa/etiología , Aterectomía Coronaria/efectos adversos , Estenosis Coronaria/cirugía , Vasos Coronarios/diagnóstico por imagen , Calcificación Vascular/cirugía , Anciano , Fístula Arteriovenosa/diagnóstico , Angiografía Coronaria , Estenosis Coronaria/diagnóstico , Humanos , Masculino , Calcificación Vascular/diagnóstico

RESUMEN

Myocardial microRNAs (myo-miRs) are released into the circulation after acute myocardial infarction (AMI). How they impact remote organs is however largely unknown. Here we show that circulating myo-miRs are carried in exosomes and mediate functional crosstalk between the ischemic heart and the bone marrow (BM). In mice, we find that AMI is accompanied by an increase in circulating levels of myo-miRs, with miR-1, 208, and 499 predominantly in circulating exosomes and miR-133 in the non-exosomal component. Myo-miRs are imported selectively to peripheral organs and preferentially to the BM. Exosomes mediate the transfer of myo-miRs to BM mononuclear cells (MNCs), where myo-miRs downregulate CXCR4 expression. Injection of exosomes isolated from AMI mice into wild-type mice downregulates CXCR4 expression in BM-MNCs and increases the number of circulating progenitor cells. Thus, we propose that myo-miRs carried in circulating exosomes allow a systemic response to cardiac injury that may be leveraged for cardiac repair.

Asunto(s)

Células Madre Hematopoyéticas/metabolismo , MicroARNs/sangre , Infarto del Miocardio/sangre , Miocardio/metabolismo , Anciano , Animales , Regulación hacia Abajo , Exosomas/metabolismo , Femenino , Movilización de Célula Madre Hematopoyética , Células Madre Hematopoyéticas/patología , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , MicroARNs/metabolismo , Persona de Mediana Edad , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Receptores CXCR4/metabolismo

RESUMEN

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a cytokine with multiple effects on the body. For one thing, TSLP induces Th2 immunoreaction and facilitates allergic reaction; for another, it promotes the differentiation of naturally occurring CD4+CD25+Foxp3+ regulatory T cells (nTregs) and maintains immune tolerance. However, the exact role of TSLP in atherosclerosis remains unknown. METHODS AND RESULTS: In vitro, we examined the phenotype of TSLP-conditioned bone marrow dendritic cells (TSLP-DCs) of apolipoprotein E-deficient (ApoE-/-) mice and their capacity to induce the differentiation of Tregs. Our results indicated that TSLP-DCs obtained the characteristics of tolerogenic dendritic cells and increased a generation of CD4+ latency-associated peptide (LAP)+ Tregs and nTregs when cocultured with naive T cells. In addition, the functional relevance of TSLP and TSLP-DCs in the development of atherosclerosis was also determined. Interestingly, we found that TSLP was almost absent in cardiovascular tissue of ApoE-/- mice, and TSLP administration increased the levels of antioxidized low-density lipoprotein IgM and IgG1, but decreased the levels of IgG2a in plasma. Furthermore, mice treated with TSLP and TSLP-DCs developed significantly fewer (32.6% and 28.2%, respectively) atherosclerotic plaques in the aortic root compared with controls, along with increased numbers of CD4+LAP+ Tregs and nTregs in the spleen and decreased inflammation in the aorta, which could be abrogated by anti-TGF-ß antibody. CONCLUSIONS: Our results revealed a protective role for TSLP in atherosclerosis that is possibly mediated by reestablishing a tolerogenic immune response, which may represent a novel possibility for treatment or prevention of atherosclerosis.

Asunto(s)

Aterosclerosis/etiología , Citocinas/fisiología , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/prevención & control , Células Cultivadas , Citocinas/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Linfocitos T Reguladores/fisiología , Células Th2/fisiología , Factor de Crecimiento Transformador beta/fisiología , Linfopoyetina del Estroma Tímico

RESUMEN

INTRODUCTION: Numerous studies suggest that total cholesterol content of erythrocyte membranes (CEM) might play a critical role in atherosclerotic plaque progression and instability. However, the exact role of CEM in atherosclerosis remains obscure. Our study was designed to investigate the association between CEM and the severity of coronary artery disease (CAD), and to assess the effect of rosuvastatin on CEM levels. METHODS: CEM levels were assessed in 136 participants, including acute coronary syndrome (ACS) (non-ST-segment elevation ACS (NSTEACS) and ST-segment elevation myocardial infarction (STEMI)), stable angina pectoris (SAP), and controls. The Gensini score was used to estimate the severity of CAD. Additionally, 54 patients with CAD were medicated with rosuvastatin, 5 or 10 mg once daily, and then checked at 6 months. RESULTS: The highest level of CEM was found in the STEMI group, followed by the NSTEACS, the SAP, and the control groups. Gensini score in group IV (CEM > 141.6 µg/mg) was markedly higher compared with group I (CEM ≤77.6 µg/mg). Gensini scores in group II (77.6 < CEM ≤111.1 µg/mg) and group III (111.1 < CEM ≤141.6 µg/mg) were also higher than in group I (all P < 0.001). Furthermore, a positive correlation was found between CEM levels and Gensini score (r = 0.714, P < 0.001). CEM levels were dose-dependently reduced by rosuvastatin therapy. CONCLUSIONS: CEM levels are positively associated with the severity of CAD, meaning that CEM might contribute to the development of CAD. Importantly, rosuvastatin could decrease CEM levels in patients with CAD and might effectively help to attenuate the progression of CAD.

Asunto(s)

Colesterol/sangre , Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/patología , Membrana Eritrocítica/metabolismo , Fluorobencenos/uso terapéutico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Pirimidinas/uso terapéutico , Sulfonamidas/uso terapéutico , Anciano , Estudios de Casos y Controles , Enfermedad de la Arteria Coronaria/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Rosuvastatina Cálcica , Índice de Severidad de la Enfermedad

RESUMEN

Increasing studies have demonstrated that atherosclerosis is a chronic immunoinflammatory disease, and that oxidized low-density lipoprotein (oxLDL)-specific T cells contribute to the autoimmune process in atherosclerosis. Oral administration of oxLDL, which was identified as a candidate autoantigen in atherosclerosis, was shown to induce tolerance and suppress atherogenesis. However, the precise mechanisms of mucosal tolerance induction, in particular nasal tolerance, remain unknown. In this study, we explored the effect of nasal oxLDL on atherosclerosis as well as the cellular and molecular mechanisms leading to atheroprotective responses, and then found that nasal oxLDL drastically ameliorate the initiation (47.6 %, p < 0.001) and progression (21.1 %, p = 0.001) of atherosclerosis. Most importantly, a significant 35.8 % reduction of the progression of atherosclerosis was observed in the enhanced immunization group (p < 0.001). These effects were accompanied by a significant increase in CD4(+) latency-associated peptide (LAP)(+) regulatory T cells (Tregs) and CD4(+)CD25(+)Foxp3(+) Tregs in spleens and cervical lymph nodes, together with increased transforming growth factor (TGF)-ß production and suppressed T-helper cells type 1, 2, and 17 immune responses. Surprisingly, neutralization of TGF-ß in vivo partially counteracted the protective effect of nasal oxLDL treatment, indicating that the presence of TGF-ß was indispensable to CD4(+)LAP(+) Tregs and CD4(+)CD25(+)Foxp3(+) Tregs to acquire regulatory properties. Our studies suggest that CD4(+)LAP(+) Tregs and CD4(+)CD25(+)Foxp3(+) Tregs induced by nasal delivery of oxLDL can inhibit oxLDL-specific T cells response and ameliorate atherosclerosis process.

Asunto(s)

Aterosclerosis/inmunología , Lipoproteínas LDL/administración & dosificación , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta/inmunología , Administración Intranasal , Animales , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/sangre , Antígenos CD4/inmunología , Colesterol/sangre , Citocinas/inmunología , Dieta Alta en Grasa , Factores de Transcripción Forkhead/inmunología , Subunidad alfa del Receptor de Interleucina-2/inmunología , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/inmunología , Masculino , Ratones , Ratones Noqueados , Bazo/citología , Bazo/efectos de los fármacos , Bazo/inmunología , Linfocitos T Colaboradores-Inductores/inmunología

RESUMEN

Mounting evidence supports that a newly identified regulatory T cell (Treg), CD4(+)LAP(+) Treg, is associated with oral tolerance induction and following inhibition of atherosclerosis, but little is described about whether nasal tolerance to antigen likewise induces the novel Tregs production and the relevant antiatherosclerotic benefit. We investigated the effect of nasal administration of heat shock protein-60 (HSP60) on atherogenesis. HSP60 or phosphate buffer solution (PBS) was nasally administered to six-week-old male ApoE(-/-) mice. At the 10th week after the nasal administration, there was a significant decrease in atherosclerotic plaque areas of aortic roots in the HSP60-treated mice as compared with those in the PBS-treated mice. Atherosclerosis suppression was accompanied with a significant increase in CD4(+)LAP(+) and CD4(+)CD25(+)Foxp3(+) Tregs and a concurrently increased production of TGF-ß in the HSP60-treated mice. The protective effect of HSP60 was offset by injection of anti-TGF-ß antibody. It is concluded that nasal administration of HSP60 can inhibit atherosclerotic formation through immune tolerance which is established by Tregs depending on the induction of anti-inflammatory cytokine TGF-ß. Immune tolerance induced by nasal administration of HSP60 may provide an alternative therapeutic method for atherosclerosis.

Asunto(s)

Aterosclerosis/inmunología , Aterosclerosis/prevención & control , Chaperonina 60/administración & dosificación , Chaperonina 60/inmunología , Tolerancia Inmunológica/inmunología , Linfocitos T Reguladores/inmunología , Factor de Crecimiento Transformador beta/inmunología , Administración Intranasal , Animales , Aterosclerosis/patología , Tolerancia Inmunológica/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Resultado del Tratamiento

RESUMEN

Mounting evidence supports that a newly identified regulatory T cell (Treg),CD4+LAP+ Treg,is associated with oral tolerance induction and following inhibition of atherosclerosis,but little is described about whether nasal tolerance to antigen likewise induces the novel Tregs production and the relevant antiatherosclerotic benefit.We investigated the effect of nasal administration of heat shock protein-60 (HSP60) on atherogenesis.HSP60 or phosphate buffer solution (PBS) was nasally adminis-tered to six-week-old male ApoE (-/-) mice.At the 10th week after the nasal administration,there was a significant decrease in atherosclerotic plaque areas of aortic roots in the HSP60-treated mice as compared with those in the PBS-treated mice.Atherosclerosis suppression was accompanied with a significant increase in CD4+LAP+ and CD4+CD25+Foxp3+ Tregs and a concurrently increased production of TGF-β in the HSP60-treated mice.The protective effect of HSP60 was offset by injection of anti-TGF-β antibody.It is concluded that nasal administration of HSP60 can inhibit atherosclerotic formation through immune tolerance which is established by Tregs depending on the induction of anti-inflammatory cytokine TGF-β.Immune tolerance induced by nasal administration of HSP60 may provide an alternative therapeutic method for atherosclerosis.

RESUMEN

BACKGROUND: CXCL16 has been shown to be involved in atherosclerotic lesion development, but its role in preexisting lesions is still unclear. This study aims to assess the effect of CXCL16 on the stability of preexisting lesions. METHODS: We firstly measured plasma CXCL16 level in Apolipoprotein E-Knockout (ApoE KO) mice with either high-cholesterol diet (HCD) or normal diet (ND) by enzyme-linked immunosorbent assay (ELISA). Then, silastic collars were placed around the carotid arteries in HCD-ApoE KO mice to accelerate atherosclerotic lesions. Five weeks later, CXCL16 was overexpressed by intravenous injection of lentivirus carrying CXCL16 transgene. Two weeks after infection, lesions were stained with hematoxylin and eosin (HE) and with oil red O. Biomarkers in the lesions, such as MMPs, CCL2, VCAM-1 and TNF-α were measured by real-time polymerase chain reaction (RT-PCR), which indicate the instability of plaques. RESULTS: The level of CXCL16 in plasma was higher in HCD-ApoE KO mice as compared to ND-ApoE KO mice. Circulating CXCL16 overexpression does not affect the size of preexisting plaques, but it leads to vulnerable plaque morphology and increases the expression of markers of plaque destabilization. CONCLUSION: Systemic CXCL16 becomes much higher in atherosclerosis, and it could be a potential atherogenic biomarker. Overexpression of CXCL16 promotes the evolution of preexisting lesions to vulnerable plaques in ApoE KO mice.

Asunto(s)

Apolipoproteínas E/deficiencia , Arterias Carótidas/metabolismo , Quimiocina CXCL6/sangre , Placa Aterosclerótica/sangre , Animales , Apolipoproteínas E/genética , Tirantes/efectos adversos , Arterias Carótidas/patología , Quimiocina CCL2/genética , Quimiocina CXCL16 , Quimiocina CXCL6/biosíntesis , Quimiocina CXCL6/genética , Colesterol en la Dieta/administración & dosificación , Colesterol en la Dieta/efectos adversos , Ensayo de Inmunoadsorción Enzimática , Expresión Génica , Masculino , Metaloproteinasas de la Matriz/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fenotipo , Placa Aterosclerótica/etiología , Placa Aterosclerótica/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transfección , Factor de Necrosis Tumoral alfa/genética , Molécula 1 de Adhesión Celular Vascular/genética

RESUMEN

BACKGROUND: The novel chemokine CXCL16 is involved in the development of atherosclerosis and coronary artery disease (CAD). However, the role of CXCL16 in atherosclerosis remains uncertain. This study was designed to investigate the relationship between CXCL16 and the severity of coronary artery stenosis. METHODS: Using ELISA, we assayed the plasma CXCL16 concentration in 16 stable angina pectoris (SAP) patients, 53 acute coronary syndrome (ACS) patients, and 19 control patients. All patients underwent coronary angiography after admission. They were divided into four groups according to the quartile of CXCL16 level. Characteristics and the relationship between CXCL16 and the elements were studied in each group. RESULTS: CXCL16 levels in the ACS group were higher than controls and SAP group (p <0.01 vs. controls; p <0.05 vs. SAP group). Gensini score in the highest quartile group of CXCL16 level (group IV, CXCL16 >2.21 ng/mL) was significantly higher than in the lowest quartile group of CXCL16 level (group I, CXCL16 < or = 1.43 ng/mL) (p <0.001). Gensini score in group II (1.43 ng/mL

Asunto(s)

Quimiocinas CXC/sangre , Estenosis Coronaria/sangre , Estenosis Coronaria/patología , Receptores Depuradores/sangre , Enfermedad Aguda , Adulto , Anciano , Anciano de 80 o más Años , Angina de Pecho/sangre , Quimiocina CXCL16 , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo