Papel de la pro-proteína convertasa subtilisina kexina de tipo 9 (pcsk9) en el macrófago. Implicaciones en el desarrollo de aterosclerosis

Abstract

Abstract Cardiovascular diseases are the main cause of death worldwide. Atherosclerosis is the underlying cause related to most of the clinical outcomes. High LDL cholesterol levels are by far the main factor that triggers the development of the disease. Macrophages are key players of the inflammatory response within the atherosclerotic lesion. In their attempt to eliminate the excess of cholesterol, the chronic inflammation induced by these worsen the plaque with the following rupture and thrombosis expressed as heart attack, ictus and other clinical events. PCSK9 is a protein produced mainly by the liver that acts regulating the LDL receptor through its degradation. Thus, mutations with gain-of-function on PCSK9 gene promote an increase in plasma LDL levels. Little is known about PCSK9 expression and function in extrahepatic tissues and organs. In the present work, we investigated the role of PCSK9 in macrophages and vascular tissues. There is no expression of this protein in macrophages, endothelium and vascular smooth muscle cells. However, the stimulation with exogenous PCSK9 promotes a degradation in LDL and CD36 receptors in macrophages. Besides, PCSK9 induced a higher production of reactive oxygen species and an increased sensibility to death in these cells. These changes are followed by a rise in the NADPH oxidase NOX2 expression and its inhibition reverts these effects made by PCSK9. Also, PCSK9 promotes a discreet increase in macrophage migration, which express high levels of CXCL1 and CD47 due to PCSK9. Finally, the expression of PCSK9 in human hypercholesterolemic serum is higher than in healthy patients and, in arteries of patients with advanced atherosclerotic lesions, there is a protein expression of PCSK9, which suggest a deposit of hepatic PCSK9 in vascular tissues, and thus promoting the development of atherosclerosis.