High-density lipoprotein: a double-edged sword in cardiovascular physiology and pathophysiology

Abstract

High-density lipoprotein (HDL) plays a central role in vascular biology. HDL participates in multiple pathways that may be involved in the development of atherosclerosis and coronary artery disease (CAD), including cholesterol removal from the tissues (including vascular arterial wall), endothelial function protection through anti-inflammatory, antioxidant and anti-apoptotic effects, endothelial repair, angiogenesis and improved endothelial cell survival. Initial epidemiological evidence supported an inverse relationship between HDL level and the risk for atherosclerosis and CAD. Although HDL showed an inverse relationship with cardiovascular risk, pharmacologically-based HDL-raising therapies and Mendelian randomization studies refuted a causal relationship between HDL and the risk for atherosclerosis and CAD. So far, no HDL-raising therapy that increased HDL level without a concomitant decrease in the low-density lipoprotein (LDL) level reduced the cardiovascular risk. HDL structure and function alterations in various morbid conditions including inflammatory states, metabolic diseases, chronic kidney disease, cardiovascular risk factors and CAD transform HDL from a vasoprotective and anti-atherosclerotic particle into a proinflammatory and pro-atherosclerotic dysfunctional equivalent. Genetic studies, failure of HDL-raising therapies to improve clinical outcome despite markedly raising HDL levels and a better understanding of HDL functions led to a paradigm shift in HDL studies from investigation of HDL concentration to investigation of HDL functions (such as, cholesterol efflux capacity and anti-inflammatory indices) as a response to various therapeutic interventions. Several therapies aiming to improve HDL functions are in clinical use or under development. Future studies are needed to assess the role of HDL in vascular biology and cardiovascular epidemiology, pathophysiology and pharmacology.