HDL function and novel HDL-targeted therapies for preventing atherosclerotic cardiovascular disease: from mouse models to human disease

Abstract

catalaMalgrat que la relacio inversa entre les concentracions baixes de colesterol associat a lipoproteines d’alta densitat i l’increment del risc de patir una malaltia cardiovascular esta comunament acceptada, l’us d’alguns farmacs que incrementen les concentracions de colesterol d’HDL no s’ha trobat associat a una reduccio en l’aparicio d’episodis cardiovasculars. Es considera que el transport revers de colesterol (RCT) es el principal responsable de l’efecte cardioprotector de l’HDL, estimulant el flux de colesterol des dels macrofags de les cel·lules escumoses en la lesio arteriosclerotica cap a fetge on es eliminat parcialment en femtes. A mes del RCT, les HDL tenen altres propietats cardioprotectores degudes als seus efectes antioxidant i antiinflamatori. Els estudis en ratolins modificats geneticament han permes demostrar que aquestes funcions de les HDL estan associades a la susceptibilitat a l’arterioesclerosi i suggereixen que farmacs que les puguin estimular podrien ser considerats com a noves estrategies terapeutiques per a prevenir el desenvolupament de la placa arterioesclerotica i el risc d’episodis cardiovasculars. El potencial antitumorogenic de les HDL es una area d’investigacio recent. Aquests tipus d’investigacions son essencials per a poder traslladar els resultats obtinguts a humans. Els estudis mes recents indiquen que l’augment del flux de colesterol des dels macrofags fins a les HDL, el primer pas del RCT, esta inversament relacionat amb l’aparicio d’episodis cardiovasculars. Per tant, la majoria d’estudis actuals van enfocats a millorar les propietats cardioprotectores de les HDL, mes que no pas a intentar augmentar les concentracions de colesterol d’HDL. EnglishAlthough significant evidence supports the concept that low high density lipoprotein cholesterol (HDL-C) is associated with an increased risk of cardiovascular disease (CVD), the failure of several HDL-targeted therapies to reduce CVD has cast doubts on the HDL-C hypothesis. Reverse cholesterol transport (RCT) is currently thought to be a major HDL cardioprotective property by which HDL promotes cholesterol efflux from macrophage foam cells and delivers that cholesterol to the liver, from where it will be partly eliminated through bile and feces. Beyond RCT, HDL exhibits other cardioprotective properties, such as antioxidant and anti-inflammatory effects. Data from genetically-engineered mice indicate that these HDL functions are closely associated with atherosclerosis susceptibility, thereby suggesting that the promotion of HDL functional properties may be considered a novel therapeutic strategy to reduce the atherosclerotic plaque burden and subsequent cardiovascular events. Furthermore, the potential anti-tumorigenic role of HDL is currently under investigation. This research has been essential for trying to translate experimental results obtained in mice to humans. The results of several recent human studies indicate that enhanced macrophage cholesterol efflux, the first step of RCT, is inversely associated with CVD events. Therefore, the current research is focused on improving HDL function rather than simply targeting HDL-C levels.