Long non-coding RNAs at the crossroad of vascular smooth muscle cell phenotypic modulation in atherosclerosis and neointimal formation

Abstract

Despite extraordinary advances in the comprehension of the pathophysiology of atherosclerosis and the employment of very effective treatments, cardiovascular diseases are still a major cause of mortality and represent a large share of health expenditure worldwide. Atherosclerosis is a disease affecting the medium and large arteries, which consists of a progressive accumulation of fatty substances, cellular waste products and fibrous elements, which culminates in the buildup of a plaque obstructing the blood flow. Endothelial dysfunction represents an early pathological event, favoring immune cells recruitment and triggering local inflammation. The release of inflammatory cytokines and other signaling molecules stimulates phenotypic modifications in the underlying vascular smooth muscle cells, which, in physiological conditions, are responsible for the maintenance of vessels architecture while regulating vascular tone. Vascular smooth muscle cells are highly plastic and may respond to disease stimuli by de-differentiating and losing their contractility, while increasing their synthetic, proliferative, and migratory capacity. This phenotypic switching is considered a pathological hallmark of atherogenesis and is ruled by the activation of selective gene programs. The advent of genomics and the improvement of sequencing technologies deepened our knowledge of the complex gene expression regulatory networks mediated by non-coding RNAs, and favored the rise of innovative therapeutic approaches targeting the non-coding transcriptome. In the context of atherosclerosis, long non-coding RNAs have received increasing attention as potential translational targets, due to their contribution to the molecular dynamics modulating the expression of vascular smooth muscle cells contractile/synthetic gene programs. In this review, we will focus on the most well-characterized long non-coding RNAs contributing to atherosclerosis by controlling expression of the contractile apparatus and genes activated in perturbed vascular smooth muscle cells.

Keywords: Atherosclerosis; Cardiovascular diseases; Long non-coding RNAs; Phenotypic switch; Smooth muscle cells.