Specialized Proresolving Lipid Mediators: A Potential Therapeutic Target for Atherosclerosis

Abstract

Cardiovascular disease (CVD) is a global public health issue due to its high morbidity, mortality, and economic impact. The implementation of innovative therapeutic alternatives for CVD is urgently required. Specialized proresolving lipid mediators (SPMs) are bioactive compounds derived from ω-3 and ω-6 fatty acids, integrated into four families: Lipoxins, Resolvins, Protectins, and Maresins. SPMs have generated interest in recent years due to their ability to promote the resolution of inflammation associated with the pathogeneses of numerous illnesses, particularly CVD. Several preclinical studies in animal models have evidenced their ability to decrease the progression of atherosclerosis, intimal hyperplasia, and reperfusion injury via diverse mechanisms. Large-scale clinical trials are required to determine the effects of SPMs in humans. This review integrates the currently available knowledge of the therapeutic impact of SPMs in CVD from preclinical and clinical studies, along with the implicated molecular pathways. In vitro results have been promising, and as such, SPMs could soon represent a new therapeutic alternative for CVD.

Keywords: atherosclerosis; inflammation; intimal hyperplasia; reperfusion injury; resolution; specialized proresolving mediators.

Figure 1

Lipoxins are derived from arachidonic acid, an ω-6 polyunsaturated fatty acid. The E-series resolvins are formed from the metabolism of the ω-3 polyunsaturated fatty eicosapentaenoic acid (EPA). Ohtter metabolites, E-series resolvins, maresins, and protectins are also formed from metabolism of the ω-3 polyunsaturated fatty acids docosahexaenoic acid (DHA). Finally, there are six known receptors belonging to the G protein-coupled receptor family for the SPMs, which are widely spread among human tissues, including leucocytes and endothelial cells. Each SPM represents a ligand for each of these receptors, frequently overlapping in matters of selectivity and biological functions. Figure 1 is presented to facilitate understanding the identified SPM receptors and the metabolic pathways involved with their proresolving biological functions, as described in murine models. AA: Arachidonic Acid. LXA4: Lipoxins A4. LXB4: Lipoxins B4. EPA: Eicosapentaenoic acid. RvE: Resolvins E series. DHA: Docosahexaenoic acid. MaR: Maresins PD1: Protectin 1. RvD: Resolvins D series. PKC: Protein kinase C. PLC: Phospholipase C. CREB: cAMP Response Element-Binding Protein. AC: adenylyl cyclase. cAMP: Cyclic adenosine monophosphate. ERK: extracellular-signal-regulated kinase. NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells. PI3K: Phosphoinositide 3-kinase.

Figure 2

It has been shown that SPM levels are decreased in atherosclerosis, which influences the progression of the disease, given their proresolution role. These molecules decrease monocyte and neutrophil adhesion, as well as rolling. Additionally, SPM reduces proinflammatory cytokine synthesis, oxidative stress, and vascular smooth muscle cell migration while promoting plaque stability, collagen synthesis, macrophage prototype M2 activation, and efferocytosis, which reduces the size of the necrotic nucleus. ATL: Aspirin triggered lipoxins. LXA4: Lipoxin A4. LXB4: Lipoxin B4. RvD1: Resolvin D. RvD2: Resolvin D2. RvD3: Resolvin D3. RvE1: Resolvin E1. MaR1: Maresin 1. NOX: Nicotinamide adenine dinucleotide phosphate-oxidase. ROS: Reactive oxygen species. O2-: Superoxide.

Figure 3

Mechanisms of actions of Specialized proresolving lipid mediators in intimal hyperplasia are involved in different processes: (1) Blocking the migration of VSMC in the intima; (2) Inhibiting the proliferation of VSMC in the intima; (3) Increasing Macrophage Polarization in the anti-inflammatory phenotype; (4) Interfering with the adhesion of neutrophils and monocytes; (5) Reducing the secretion of proinflammatory cytokines; (6) Decreasing production of ROS by NOX. IL-1: Interleukine 1. IL-6: Interleukine 6. TNF-α: Tumor Necrosis Factor Alfa. M1: Classically activated macrophages. M2: Alternatively activated macrophages. RvD: Resolvins D Serie. MaR: Maresins. RvE: Resolvins E Serie. ATL: Aspirin-triggered lipoxin. NOX: Nicotinamide adenine dinucleotide phosphate-oxidase ROS: Reactive oxygen species. O2-: Superoxide. VCAM-1: Vascular cell adhesion molecule 1 ICAM-1: Intercellular adhesion molecule 1.