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1.
Basic Res Cardiol ; 118(1): 33, 2023 08 28.
Artículo en Inglés | MEDLINE | ID: mdl-37639039

RESUMEN

While low concentrations of high-density lipoprotein-cholesterol (HDL-C) are widely accepted as an independent cardiovascular risk factor, HDL-C-rising therapies largely failed, suggesting the importance of both HDL functions and individual subspecies. Indeed HDL particles are highly heterogeneous, with small, dense pre-beta-HDLs being considered highly biologically active but remaining poorly studied, largely reflecting difficulties for their purification. We developed an original experimental approach allowing the isolation of sufficient amounts of human pre-beta-HDLs and revealing the specificity of their proteomic and lipidomic profiles and biological activities. Pre-beta-HDLs were enriched in highly poly-unsaturated species of phosphatidic acid and phosphatidylserine, and in an unexpectedly high number of proteins implicated in the inflammatory response, including serum paraoxonase/arylesterase-1, vitronectin and clusterin, as well as in complement regulation and immunity, including haptoglobin-related protein, complement proteins and those of the immunoglobulin class. Interestingly, amongst proteins associated with lipid metabolism, phospholipid transfer protein, cholesteryl ester transfer protein and lecithin:cholesterol acyltransferase were strongly enriched in, or restricted to, pre-beta-HDL. Furthermore, pre-beta-HDL potently mediated cellular cholesterol efflux and displayed strong anti-inflammatory activities. A correlational network analysis between lipidome, proteome and biological activities highlighted 15 individual lipid and protein components of pre-beta-HDL relevant to cardiovascular disease, which may constitute novel diagnostic targets in a pathological context of altered lipoprotein metabolism.


Asunto(s)
Enfermedades Cardiovasculares , Humanos , Proteómica , HDL-Colesterol , Factores de Riesgo de Enfermedad Cardiaca , Metabolismo de los Lípidos
2.
Expert Opin Ther Pat ; 26(12): 1377-1392, 2016 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-27359211

RESUMEN

INTRODUCTION: The identification by Abifadel et al. in 2003 of the first mutations of PCSK9 was the major breakthrough in the cholesterol field that led to a new therapeutic target. This discovery paved the way to new lipid lowering drugs reducing LDL-cholesterol levels through the inhibition of PCSK9. Two anti-PCSK9 monoclonal antibodies have received FDA and EMA approvals: Alirocumab and Evolocumab. Areas covered: This article reviews the different strategies that are pursued to modulate the functional activity of PCSK9 for lowering LDL-cholesterol levels. It also provides a brief overview of the patents related to PCSK9 from 2011 until the end of 2015. This review is addressed to researchers from academia and pharmaceutical companies who are engaged in PCSK9 research/cholesterol regulation. Readers will gain an up-to-date overview of the different strategies that have been investigated to reduce PCSK9, focusing on anti-PCSK9 monoclonal antibodies and the related clinical trials. Expert opinion: Anti-PCSK9 antibodies are a new class of lipid lowering drugs with promising results in reducing LDL-cholesterol. Long-term ongoing studies investigating on a large scale the efficacy and safety of the anti-PCSK9 antibodies and their cardiovascular outcomes are eagerly awaited.


Asunto(s)
Anticolesterolemiantes/farmacología , Dislipidemias/tratamiento farmacológico , Inhibidores de PCSK9 , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados , LDL-Colesterol/sangre , Diseño de Fármacos , Dislipidemias/genética , Dislipidemias/patología , Humanos , Mutación , Patentes como Asunto , Proproteína Convertasa 9/genética
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