RESUMEN
Oxidized low density lipoprotein (oxLDL)-induced endothelial oxidative damage promotes the development of atherosclerosis. Caveolae play an essential role in maintaining the survival and function of vascular endothelial cell (VEC). It is reported that the long coiled-coil protein NECC2 is localized in caveolae and is associated with neural cell differentiation and adipocyte formation, but its role in VECs needs to be clarified. Our results showed NECC2 expression increased in the endothelium of plaque-loaded aortas and oxLDL-treated HUVECs. Down-regulation of NECC2 by NECC2 siRNA or compound YF-307 significantly inhibited oxLDL-induced VEC apoptosis and the adhesion factors expression. Remarkably, inhibition of NECC2 expression in the endothelium of apoE-/- mice by adeno-associated virus (AAV)-carrying NECC2 shRNA or compound YF-307 alleviated endothelium injury and restricted atherosclerosis development. The immunoprecipitation results confirmed that NECC2 interacted with Tyk2 and caveolin-1(Cav-1) in VECs, and NECC2 further promoted the phosphorylation of Cav-1 at Tyr14 b y activating Tyk2 phosphorylation. On the other hand, inhibiting NECC2 levels suppressed oxLDL-induced phosphorylation of Cav-1, uptake of oxLDL by VECs, accumulation of intracellular reactive oxygen species and activation of NF-κB. Our findings suggest that NECC2 may contribute to oxLDL-induced VEC injury and atherosclerosis via modulating Cav-1 phosphorylation through Tyk2. This work provides a new concept and drug target for treating atherosclerosis.
Asunto(s)
Aterosclerosis , Animales , Ratones , Apolipoproteínas/efectos adversos , Apolipoproteínas/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerosis/metabolismo , Endotelio/metabolismo , Lipoproteínas LDL/metabolismo , Estrés OxidativoRESUMEN
BACKGROUND: Abdominal aortic aneurysm (AAA) is an arterial disease characterized by dilatation of the aortic wall. It has been suggested that neutrophil counts and neutrophil elastase activity are associated with AAA. We investigated whether a neutrophil elastase (NE) inhibitor, sivelestat (Siv), had a protective effect against angiotensin II (AngII)-induced AAAs. METHODS: Male apolipoprotein E-deficient mice were assigned into three groups: Vehicleâ +â saline, AngIIâ +â saline, and AngIIâ +â Siv. All mice were administered intraperitoneally with either Siv or vehicle twice daily after AngII infusion. RESULTS: In the 4-week AngII infusion study, plasma NE concentration (Pâ =â 0.041) and its activity (Pâ =â 0.011) were elevated by AngII. These increases were attenuated by Siv (concentration:Pâ =â 0.010, activity:Pâ =â 0.027). Further, plasma elastase activity was closely correlated with aortic width (Râ =â 0.6976, Pâ <â 0.001). In the 1-week AngII infusion study, plasma and tissue elastase activity increased by AngII (plasma:Pâ =â 0.034, tissue:Pâ <â 0.001), but were reduced by Siv (plasma:Pâ =â 0.014, tissue:Pâ =â 0.024). AngII increased aortic width (Pâ =â 0.011) but was attenuated by co-administration of Siv (Pâ =â 0.022). Moreover, Siv decreased the incidence of AAAs (Pâ =â 0.009). Elastin fragmentation induced by AngII was reduced by Siv. Many inflammatory cells that were either CD68 or Gr-1 positive were observed in the AngIIâ +â saline group, whereas few inflammatory cells were accumulated in the AngIIâ +â Siv group. MMP-2 and MMP-9 were enhanced by AngII, but were reduced by Siv. In vitro, MMP-2 activity was induced by human NE (medium:Pâ <â 0.001, cells:Pâ =â 0.001), which was attenuated by co-incubation of Siv in medium (Pâ <â 0.001) and protein of human aortic smooth muscle cells (Pâ =â 0.001). CONCLUSIONS: Siv attenuated AngII-induced AAA through the inhibition of NE.
Asunto(s)
Angiotensina II , Aneurisma de la Aorta Abdominal , Glicina/análogos & derivados , Sulfonamidas , Humanos , Masculino , Ratones , Animales , Angiotensina II/farmacología , Metaloproteinasa 2 de la Matriz/metabolismo , Elastasa de Leucocito/efectos adversos , Elastasa de Leucocito/metabolismo , Ratones Noqueados , Aneurisma de la Aorta Abdominal/inducido químicamente , Aneurisma de la Aorta Abdominal/prevención & control , Apolipoproteínas/efectos adversos , Apolipoproteínas/metabolismo , Ratones Endogámicos C57BL , Aorta Abdominal/metabolismo , Modelos Animales de EnfermedadRESUMEN
Apolipoprotein E (ApoE) is a corticosteroid-unresponsive gene that negatively regulates ovalbumin (OVA) -induced allergic airway inflammation in mice with acute asthma. However, whether ApoE negatively regulates airway remodeling in mice with OVA-induced chronic asthma remains unknown. This study aimed to investigate the effects of ApoE on OVA-induced chronic asthma in a murine model. ApoE knockout (ApoE-/-) and wild-type (WT) mice were sensitized and challenged with OVA for 10 weeks to establish the chronic asthma model. Compared with WT mice, the results demonstrated that ApoE deficiency exacerbated OVA-induced airway inflammation, including elevated numbers of inflammatory cells in the blood and bronchoalveolar lavage fluid (BALF), as well as increased T helper type 2 (Th2) cells in lung tissue, Th2 cytokines in BALF, and total IgE levels in plasma. Importantly, ApoE deficiency aggravated OVA-induced airway remodeling, as evidenced by higher plasma transforming growth factor (TGF)-ß1 levels, airway goblet cell hyperplasia, and collagen deposition compared with WT mice. These results revealed that ApoE deficiency aggravates airway remodeling and inflammation in mice with OVA-induced chronic allergic asthma.
Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias) , Asma , Animales , Ratones , Ovalbúmina/metabolismo , Líquido del Lavado Bronquioalveolar , Asma/metabolismo , Pulmón/metabolismo , Inflamación/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Apolipoproteínas/efectos adversos , Apolipoproteínas/metabolismo , Modelos Animales de Enfermedad , Ratones Endogámicos BALB CRESUMEN
PURPOSE OF REVIEW: Coronary heart disease remains the most common cause of death among women. This review summarizes observational studies of lipoproteins and coronary heart disease risk and randomized trials of lipid-lowering therapy among women and reviews progress in the implementation of proven therapies in clinical practice. RECENT FINDINGS: Recent studies confirm the strong relationship between lipoproteins and coronary heart disease development among women and extend these observations to more diverse populations. The apoprotein B/A-1 ratio is emerging as the strongest marker of coronary heart disease risk while enthusiasm for the importance of small dense LDL particles appears to be waning. International observational data re-affirm the importance of traditional risk factors in coronary heart disease development. Recent clinical trials suggest that intensive therapy with statins may provide incremental benefits. While there is progress in awareness, treatment and control of dyslipidemia, substantial proportions of women (and men) remain untreated or undertreated in the US and elsewhere. SUMMARY: Dyslipidemia and coronary heart disease risk among women are closely linked. The benefits of lipid-lowering treatment are well documented, but the full potential of such therapies has yet to be realized, in part due to delayed diagnosis of dyslipidemia, underutilization of therapy by providers, and poor adherence to treatment among patients.
Asunto(s)
Enfermedad Coronaria/tratamiento farmacológico , Dislipidemias/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipolipemiantes/uso terapéutico , Apolipoproteínas/efectos adversos , Apolipoproteínas/efectos de los fármacos , Biomarcadores , Enfermedad Coronaria/diagnóstico , Enfermedad Coronaria/fisiopatología , Dislipidemias/diagnóstico , Dislipidemias/fisiopatología , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hipolipemiantes/farmacología , Cooperación del Paciente , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Serum lipoprotein(a) [Lp(a)] concentrations and apolipoprotein(a) apo(a) phenotypes were determined in 81 hemodialysis (HD) patients, 37 chronic ambulatory peritoneal dialysis (CAPD) patients, 25 post-transplant patients and 99 healthy subjects as the reference group. The CAPD patients had significantly higher serum Lp(a) concentration than HD patients, but both had significantly increased Lp(a) levels as compared with the reference group and post-transplant patients. When all studied groups were divided into two subgroups with at least one low molecular weight (LMW) isoform and with only one high molecular weight (HMW) isoform, they presented a similar distribution. (Pearson's chi-squared = 2,78; df = 3; p = NS). The median serum Lp(a) levels were significantly increased with HMW class versus the reference group and post-transplant patients. In CAPD patients, the LMW phenotypes showed significantly increased median serum Lp(a) concentrations versus the reference group, but they were not statistically elevated in HD patients. In the post-transplant patients, LMW and HMW phenotypes did not differ as compared to the reference group. The elevated Lp(a) levels in HD and CAPD groups were explained by apo(a) type-specific, but not by differences in, isoform frequencies. We conclude that HD and CAPD patients had increased Lp(a) levels compared with the reference group, whereas elevated Lp(a) concentrations were observed mainly in patients with HMW apo(a) phenotypes. Patients after renal transplantation showed a correction of Lp(a) levels mainly in HMW phenotypes. The LMW status corresponding to high Lp(a) levels and apo(a) isoforms could be used together with Lp(a) levels with other risk factors to assess in uremic patients the predisposition to coronary artery disease.
Asunto(s)
Apolipoproteínas/sangre , Apolipoproteínas/genética , Enfermedades Cardiovasculares/etiología , Enfermedades Renales/sangre , Enfermedades Renales/genética , Trasplante de Riñón/efectos adversos , Lipoproteína(a)/sangre , Lipoproteína(a)/genética , Diálisis Peritoneal Ambulatoria Continua/efectos adversos , Fenotipo , Diálisis Renal/efectos adversos , Adulto , Anciano , Apolipoproteínas/efectos adversos , Apoproteína(a) , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/genética , Femenino , Estudios de Seguimiento , Humanos , Enfermedades Renales/terapia , Lipoproteína(a)/efectos adversos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
The incorporation of apolipoprotein E isolated from human very low density lipoproteins on a triglyceride emulsion produced a substantial increment in hepatic triglyceride after 1 h of in vitro perfusion through the isolated liver of a fasted rat. Both gross and microscopic morphology confirmed a substantial steatosis. Perfusions with triglyceride emulsions which contained no apoipoproteins resulted in a modest increment in hepatic triglyceride although considerably less than emulsions with the E protein, and no morphologic features of steatosis. The steatosis induced in the in vitro perfused fasted livers by the emulsions with E protein could be prevented when CIII-1 apoprotein was also incorporated on the emulsion. A fed rat liver perfused with the E-enriched emulsion accumulated significantly less triglyceride than the fasted preparation. These data suggest that the apoprotein patterns of the plasma triglyceride-rich lipoproteins are of considerable importance for the partition of triglyceride between liver and plasma.