Abstract
Atherosclerosis is a chronic progressive inflammatory disease where advanced lesions can eventually completely obstruct blood flow resulting in clinical events, such as a myocardial infarction or stroke. Monocytes and macrophages are the dominant biologically active immune cells involved in atherosclerosis disease and play a pivotal role during initiation, progression, and regression of disease. Altering macrophage inflammation is critical to induce regression of atherosclerosis and microRNAs (miRs) have emerged as key regulators of the macrophage phenotype. MiRs are small noncoding RNAs that regulate gene expression. They are dysregulated during atherosclerosis development and are key regulators of macrophage function and polarization. MiRs are short nucleotide transcripts that are very stable in circulation and thus have potential as therapeutics and/or biomarkers in the context of atherosclerosis. Of relevance to this review is that inhibition of macrophage-specific miR-155 may be a viable therapeutic strategy to decrease inflammation associated with atherosclerosis. However, further studies on these miRs and advancements in miR therapeutic delivery are required for these therapeutics to advance to the clinical setting. Conjugated linoleic acid (CLA), a pro-resolving lipid mediator, is an agonist of the peroxisome proliferator-activated receptor (PPAR)-γ. The biological activities of CLA have been documented to have anti-atherogenic effects in experimental models of atherosclerosis, inducing regression and impacting on monocyte and macrophage cells. Our work and that of others on PPAR-γ agonists and polyunsaturated fatty acids have shown that these mediators regulate candidate miRNAs and promote pro-resolving atherosclerotic plaque microenvironments.
Highlights
ATHEROSCLEROSIS AND INFLAMMATIONInflammation plays a pivotal role in atherosclerosis disease progression. Modified lipids such as oxidized low-density lipoprotein (oxLDL) cholesterol stimulate endothelial cell (EC) to secrete pro-inflammatory mediators including cytokines and adhesion molecules which facilitate monocyte adhesion and subsequent migration, resulting in macrophage differentiation and expansion
Diabetes Complications Research Centre, School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin, Ireland
Conjugated linoleic acid (CLA) is a generic term denoting a group of naturally occurring isomers of linoleic acid (18:2, n6), that differ in the position or geometry [i.e., cis (c) or trans (t)]
Summary
Inflammation plays a pivotal role in atherosclerosis disease progression. Modified lipids such as oxidized low-density lipoprotein (oxLDL) cholesterol stimulate ECs to secrete pro-inflammatory mediators including cytokines and adhesion molecules which facilitate monocyte adhesion and subsequent migration, resulting in macrophage differentiation and expansion. Classical or pro-inflammatory Mo1 monocytes represent 80–90% of the monocyte population and are typically described as CD14++ CD16− in humans (Ley et al, 2011) or Ly6C+ in mice (Swirski et al, 2007) Upon stimulation, they secrete high levels of interleukin (IL)-10 (Swirski et al, 2007), and activation with toll-like receptor 4 agonists results in the secretion of tumor necrosis factor (TNF)-α, IL-6, and IL-1β (Ley et al, 2011; Italiani and Boraschi, 2014), whereas stimulation with a toll-like receptor 3 agonist results in interferon (IFN)-α secretion. This suggests that M2 macrophages mediate pro-resolving roles in the clearance of apoptotic cells in early atherosclerosis but may play a role in plaque destabilization in later stages of disease
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