PCSK9 in the development of human atherosclerosis

Abstract

PCSK9 is the third gene involved in familial hypercholesterolemia, a major cause of atherosclerosis. Its role in the regulation of liver LDL receptors and plasma cholesterol levels has been widely reported and anti-PCSK9 drugs are developed. Nevertheless, interactions between PCSK9 and atherosclerotic pathology in human are not yet studied. Our aim is to demonstrate that PCSK9 could promote atherosclerosis through smooth muscle cells (SMC) involved in foam cells formation, atherosclerosis initiation and progression. Healthy and atheromatous (fatty streaks or fibrolipidic lesions) human aorta and coronary arteries are collected in accordance with ethical guidelines (Biobanque Cardiovasculaire BRIF: BB-0033-00029/BBMRI-EU/Infrastructure BIOBANQUE–CODECOH 2018-3141). Classical techniques for tissues, cells and RNA analysis were used. RT-PCR performed on RNA from tissues demonstrates that PCSK9 is not synthesized in the arterial wall. Histochemical studies and immunostaining show specific signal of PCSK9 in fatty streaks and fibrolipidic lesions compared to healthy tissues. PCSK9 is intracellularly localized, particularly in foam cells. ELISA on conditioned media show that PCSK9 concentration is significantly higher in atheromatous aortas compared to healthy ones. These data demonstrate that circulating PCSK9 synthesized by the liver penetrates the arterial wall by inward convection, especially when the wall is rich in LDL. The mechanism of PCSK9 endocytosis by human SMC and the role of scavenger receptors are under exploration. Characterization of PCSK9 within the arterial wall with its potential implication in atherosclerosis progression will contribute in a better understanding of the disease underlying mechanisms and reveal new indications for PCSK9 inhibitors.