LRP1-Mediated AggLDL Endocytosis Promotes Cholesteryl Ester Accumulation and Impairs Insulin Response in HL-1 Cells

The cardiovascular disease (CVD) frequently developed during metabolic syndrome and type-2 diabetes mellitus is associated with increased levels of aggregation-prone small LDL particles. Aggregated LDL (aggLDL) internalization is mediated by low-density lipoprotein receptor-related protein-1 (LRP1) promoting intracellular cholesteryl ester (CE) accumulation. Additionally, LRP1 plays a key function in the regulation of insulin receptor (IR) and glucose transporter type 4 (GLUT4) activities. Nevertheless, the link between LRP1, CE accumulation, and insulin response has not been previously studied in cardiomyocytes. We aimed to identify mechanisms through which aggLDL, by its interaction with LRP1, produce CE accumulation and affects the insulin-induced intracellular signaling and GLUT4 trafficking in HL-1 cells. We demonstrated that LRP1 mediates the endocytosis of aggLDL and promotes CE accumulation in these cells. Moreover, aggLDL reduced the molecular association between IR and LRP1 and impaired insulin-induced intracellular signaling activation. Finally, aggLDL affected GLUT4 translocation to the plasma membrane and the 2-NBDG uptake in insulin-stimulated cells. We conclude that LRP1 is a key regulator of the insulin response, which can be altered by CE accumulation through LRP1-mediated aggLDL endocytosis

LRP1-Mediated AggLDL Endocytosis Promotes Cholesteryl Ester Accumulation and Impairs Insulin Response in HL-1 Cells

The cardiovascular disease (CVD) frequently developed during metabolic syndrome and type-2 diabetes mellitus is associated with increased levels of aggregation-prone small LDL particles. Aggregated LDL (aggLDL) internalization is mediated by low-density lipoprotein receptor-related protein-1 (LRP1) promoting intracellular cholesteryl ester (CE) accumulation. Additionally, LRP1 plays a key function in the regulation of insulin receptor (IR) and glucose transporter type 4 (GLUT4) activities. Nevertheless, the link between LRP1, CE accumulation, and insulin response has not been previously studied in cardiomyocytes. We aimed to identify mechanisms through which aggLDL, by its interaction with LRP1, produce CE accumulation and affects the insulin-induced intracellular signaling and GLUT4 trafficking in HL-1 cells. We demonstrated that LRP1 mediates the endocytosis of aggLDL and promotes CE accumulation in these cells. Moreover, aggLDL reduced the molecular association between IR and LRP1 and impaired insulin-induced intracellular signaling activation. Finally, aggLDL affected GLUT4 translocation to the plasma membrane and the 2-NBDG uptake in insulin-stimulated cells. We conclude that LRP1 is a key regulator of the insulin response, which can be altered by CE accumulation through LRP1-mediated aggLDL endocytosisThis work was funded by Secretaría de Ciencia y Tecnología de la Universidad Nacional de Córdoba (SECyT-UNC) grants 2016 and 2017 (to GAC); Fondo para la Investigación Científica y Tecnológica (FONCyT), Préstamo BID Proyecto de Investigación en Ciencia y Tecnología (PICT) grant 2012-2607 and grant 2015-0807 (to GAC); FISPI18/01584 (to VLl-C) from Instituto Salud Carlos III, co-financed by the European Fund for Regional Development (E.F.R.D.) and by Project 201521-10 from Fundació MARATÓ TV3 (to VLl-C). CIBER Cardiovascular (CB16/11/00403 to VLl-C and DdG-C) is a project from Instituto de Salud Carlos III. VAD and MV are doctoral fellows at CONICET, and GRB and GAC are members of the Research Career of CONICET. DdG-C was a recipient of a Juan de la Cierva-Incorporación grant from the Ministerio de Economía y Competitividad (IJCI-2016-29393). DdG, AB-A are members and VLl-C is the PI of Quality Research Group (2017-SGR-946) from Generalitat de Catalunya. VLl-C anPeer reviewe

Targeting cholesteryl ester accumulation in the heart improves cardiac insulin response

International audienceBackgroundAntibodies against the P3 sequence (Gly1127-Cys1140) of LRP1 (anti-P3 Abs) specifically block cholesteryl ester (CE) accumulation in vascular cells. LRP1 is a key regulator of insulin receptor (InsR) trafficking in different cell types. The link between CE accumulation and the insulin response are largely unknown. Here, the effects of P3 peptide immunization on the alterations induced by a high-fat diet (HFD) in cardiac insulin response were evaluated.MethodsIrrelevant (IrP)- or P3 peptide-immunized rabbits were randomized into groups fed either HFD or normal chow. Cardiac lipid content was characterized by thin-layer chromatography, confocal microscopy, and electron microscopy. LRP1, InsR and glucose transporter type 4 (GLUT4) levels were determined in membranes and total lysates from rabbit heart. The interaction between InsR and LRP1 was analyzed by immunoprecipitation and confocal microscopy. Insulin signaling activity and glucose uptake were evaluated in HL-1 cells exposed to rabbit serum from the different groups.FindingsHFD reduces cardiac InsR and GLUT4 membrane levels and the interactions between LRP1/InsR. Targeting the P3 sequence on LRP1 through anti-P3 Abs specifically reduces CE accumulation in the heart independently of changes in the circulating lipid profile. This restores InsR and GLUT4 levels in cardiac membranes as well as the LRP1/InsR interactions of HFD-fed rabbits. In addition, anti-P3 Abs restores the insulin signaling cascade and glucose uptake in HL-1 cells exposed to hypercholesterolemic rabbit serum

Surgical treatment of isolated tricuspid valve infective endocarditis:25-year results from a multicenter registry

To assess early and late mortality in patients with isolated acute tricuspid valve infective endocarditis (TVIE) using data from a multicenter registry

Infective Endocarditis following Transcatheter Aortic Valve Replacement: Comparison of Balloon-Versus Self-Expandable Valves

Background: No data exist about the characteristics of infective endocarditis (IE) post-transcatheter aortic valve replacement (TAVR) according to transcatheter valve type. We aimed to determine the incidence, clinical characteristics, and outcomes of patients with IE post-TAVR treated with balloon-expandable valve (BEV) versus self-expanding valve (SEV) systems. Methods: Data from the multicenter Infectious Endocarditis After TAVR International Registry was used to compare IE patients with BEV versus SEV. Results: A total of 245 patients with IE post-TAVR were included (SEV, 47%; BEV, 53%). The timing between TAVR and IE was similar between groups (SEV, 5.5 [1.2-15] months versus BEV, 5.3 [1.7-11.4] months; P=0.89). Enterococcal IE was more frequent in the SEV group (36.5% versus 15.4%; P<0.01), and vegetation location differed according to valve type (stent frame, SEV, 18.6%; BEV, 6.9%; P=0.01; valve leaflet, SEV, 23.9%; BEV, 38.5%; P=0.01). BEV recipients had a higher rate of stroke/systemic embolism (20.0% versus 8.7%, adjusted OR: 2.46, 95% CI: 1.04-5.82, P=0.04). Surgical explant of the transcatheter valve (SEV, 8.7%; BEV, 13.8%; P=0.21), and in-hospital death at the time of IE episode (SEV, 35.6%; BEV, 37.7%; P=0.74) were similar between groups. After a mean follow-up of 13\ub112 months, 59.1% and 54.6% of the SEV and BEV recipients, respectively, had died (P=0.66). Conclusions: The characteristics of IE post-TAVR, including microorganism type, vegetation location, and embolic complications but not early or late mortality, differed according to valve type. These results may help to guide the diagnosis and management of IE and inform future research studies in the field