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Trabajo presentado en el XXXIV Congreso de la Sociedad Española de Arteriosclerosis, celebrado en Madrid (España), del 8 al 10 de junio de 2022, Background: The LRP1 (CR9) domain and, in particular, the sequence Gly1127-Cys1140 (P3) plays a critical role in the binding and internalization of aggregated LDL (agLDL). We aimed to evaluate whether immunization with P3 reduces high-fat diet (HFD)-induced atherosclerosis. Methods: Female New Zealand White (NZW) rabbits were immunized with a primary injection and four reminder doses (R1-R4) of IrP (irrelevant peptide) or P3 conjugated to the carrier. IrP and P3-immunized rabbits were randomly divided into a normal diet group and a HFD-fed group. Anti-P3 antibody levels were determined by ELISA. Lipoprotein profile, circulating and tissue lipids, and vascular pro-inflammatory mediators were determined using standardized methods while atherosclerosis was determined by confocal microscopy studies and non-invasive imaging (PET/CT and Doppler ultrasonography). Studies treating human macrophages (hM¿) and coronary vascular smooth muscle cells (hcVSMC) with rabbit serums were performed to ascertain the potential impact of anti-P3 Abs on the functionality of these crucial cells. Results: P3 immunization specifically induced the production of anti-P3 antibodies (Abs) and did not alter the lipoprotein profile. HFD strongly induced cholesteryl ester (CE) accumulation in the aorta of both the control and IrP groups, and their serum dose-dependently raised the intracellular CE of hM¿ and hcVSMC, promoting TNFR1 and phospho-NF-kB (p65) overexpression. These HFD pro-inflammatory effects were dramatically decreased in the aorta of P3-immunized rabbits and in hM¿ and hcVSMC exposed to the P3 rabbit serums. Microscopy studies revealed that P3 immunization reduced the percentage of lipids, macrophages, and SMCs in the arterial intima, as well as the atherosclerotic extent and lesion area in the aorta. PET/CT and Doppler ultrasonography studies showed that the average standardized uptake value (SUVmean) of the aorta and the arterial resistance index (ARI) of the carotids were more upregulated by HFD in the control and IrP groups than the P3 group. Conclusions: P3 immunization counteracts HFD-induced fatty streak formation in rabbits. The specific blockade of the LRP1 (CR9) domain with Anti-P3 Abs dramatically reduces HFD-induced intracellular CE loading and harmful coupling to pro-inflammatory signaling in the vasculature.

The results of the isotopic analyses performed on human remains from the Chalcolithic necropolis of Los Millares are presented in this paper. These are contextualized chronologically by a series of radiocarbon dates and, a review of the graves’ relative chronology. The dates show the megalithic necropolis was in use all along the occupation period of Los Millares, at least from 3100/3000 to 2200/2100 cal BC. The isotopic analysis results support the proposals for increasing aridity from 2400/2300 cal BC onwards. Diet is mainly based on land resources, proteins being usually taken from herbivores. However, a certain variability is found among sampled individuals because some of them may have consumed others products., [ES] Se presentan en este estudio los resultados de los análisis isotópicos realizados sobre una muestra de restos humanos de la necrópolis calcolítica de Los Millares. Para proceder a su discusión se ha realizado previamente su contextualización cronológica a partir de una serie de dataciones radiocarbónicas y la revisión de la cronología relativa de los sepulcros. Las dataciones muestran el uso de la necrópolis megalítica durante todo el periodo de ocupación de Los Millares, al menos desde 3100/3000 hasta 2200/2100 cal AC. Los resultados del análisis isotópico apoyan las propuestas sobre un incremento en la aridez desde el 2400/2300 cal AC. Además, en una dieta dominada por los recursos terrestres en la que las proteínas suelen proceder del consumo de herbívoros, existe una cierta variabilidad con individuos que pueden haber consumido otros recursos.