ALUminating the Path of Atherosclerosis Progression: Chaos Theory Suggests a Role for Alu Repeats in the Development of Atherosclerotic Vascular Disease

Abstract

Atherosclerosis (ATH) and coronary artery disease (CAD) are chronic inflammatory diseases with an important genetic background; they derive from the cumulative effect of multiple common risk alleles, most of which are located in genomic noncoding regions. These complex diseases behave as nonlinear dynamical systems that show a high dependence on their initial conditions; thus, long-term predictions of disease progression are unreliable. One likely possibility is that the nonlinear nature of ATH could be dependent on nonlinear correlations in the structure of the human genome. In this review, we show how chaos theory analysis has highlighted genomic regions that have shared specific structural constraints, which could have a role in ATH progression. These regions were shown to be enriched with repetitive sequences of the Alu family, genomic parasites that have colonized the human genome, which show a particular secondary structure and are involved in the regulation of gene expression. Here, we show the impact of Alu elements on the mechanisms that regulate gene expression, especially highlighting the molecular mechanisms via which the Alu elements alter the inflammatory response. We devote special attention to their relationship with the long noncoding RNA (lncRNA); antisense noncoding RNA in the INK4 locus (ANRIL), a risk factor for ATH; their role as microRNA (miRNA) sponges; and their ability to interfere with the regulatory circuitry of the (nuclear factor kappa B) NF-κB response. We aim to characterize ATH as a nonlinear dynamic system, in which small initial alterations in the expression of a number of repetitive elements are somehow amplified to reach phenotypic significance.

ANRIL and atherosclerosis

“…ALU elements are a family of primate‐specific short interspersed repeat elements (SINEs) and are linked with AS through facilitating the adhesion and proliferation of mononuclear cells . The functional relevance of ALU motifs in ANRIL was confirmed by deletion . Hold et al found that ANRIL (with ALU elements) facilitated adhesion and proliferation of mononuclear cells, thus aggravating the development of AS (Figure ).…”

“…54,55 65 The functional relevance of ALU motifs in ANRIL was confirmed by deletion. 66,67 Hold et al 68 found that ANRIL (with ALU elements) facilitated adhesion and proliferation of mononuclear cells, thus aggravating the development of AS (Figure 3). which inhibited the AMPK/SIRT1 signalling pathway.…”

Unveiling ncRNA regulatory axes in atherosclerosis progression

“…Atherosclerosis (ATH) is a complex inflammatory disease of the vessel wall caused by a combination of multiple factors including genomics, epigenetic modifications and environmental conditions, that place an enormous burden on modern societies, particularly in the aging population [1]. The complexity of its causes and mechanisms makes ATH prevention and treatment largely ineffective, becoming an enormous challenge for our society, favored by our lifestyle [2,3].…”

Analytical Value of Cell-Free DNA Based on Alu in Psychiatric Disorders

“…The injection of ApoExos containing unedited Alu repeats resulted in inflammation in mice (26). Alu had an influence on the inflammatory response mechanisms of atherosclerosis and coronary artery disease (53). The formation of NLRP3 inflammasome and upregulation of IL-18 and IL-1b subsequently were activated by the accumulation of Alu transcripts (36,37).…”