**11. Maresins**

Maresins, macrophage mediators in resolving inflammation are made from the ω-3 fatty acid DHA. The key enzyme in the synthesis of maresins is 12-LOX and is synthesized mainly by M2 macrophages [50,51]. Maresins appear to be tightly linked with macrophage dependent cardiac tissue regeneration and act as pro-resolving mediators by augmenting the secretion of TGF-β and decreasing concentrations of IL-6 and TNFα [52]. MaR1 synthesized by macrophages act on BLT1 and Leucine-rich repeat -containing G-protein-coupled receptor 6 (LGR6) receptors to stimulate the phenotypic transition of macrophages from pro-inflammatory M1 to pro-resolving M2 [52,53]. In addition, MaR1 acts on retinoic acidrelated orphan receptorα (ROR α) and LGR6 to enhance efferocytosis and phagocytosis by stimulating phosphorylation of several proteins such as extracellular signal-regulated kinase (ERK) and cAMP responsive element-binding protein (CREB1) [50,54,55]. In a study conducted on human saphenous vein EC and VSMC in vitro, Chatterjee and colleagues found that MaR1 weakened TNFα induced monocyte adhesion by downregulating the cell surface adhesion molecule E-selectin. However, VCAM-1 and ICAM-1 expressions remained unchanged. MaR1 also reduced ROS generation in both EC and VSMC by downregulating NADPH oxidases (NOX4, NOX1, NOX2). Because cell adhesion, and the creation of ROS, are a couple of the hallmark events in inflammation, by minimizing them, MaR1 is a SPM that stop polymorphonuclear infiltration and inhibit ROS product. Blockage of TNFα induction was discovered to be through inhibition of I-κ Kinase (IKK) phosphorylation and, eventually, the reduction in the nuclear translocation of the p65 subunit of NF-κB as mentioned above. Phosphorylation of IKK, in turn, phosphorylates and subjects I-kappa α to proteasomal degradation, resulting in the release of p65 from its I-κ complex, which then migrates to the nucleus to act as a transcription factor. NF-κB has been well established as a key transcription factor in synthesizing many pro-inflammatory

molecules that act in a paracrine way to stimulate local inflammation [56]. It has been shown that Aspirin enables the production of Aspirin-Triggered Lipoxin (ATL), a Lipoxin A4 epimer, by interacting with the receptors FPR2/ALX found on VSMCs and macrophages in atherosclerotic plaques. The presence of these receptors correlated negatively with the clinical manifestation of the disease, implying a more stable plaque, possibly through increased collagen and decreased collagenases [57]. However, MaR1 has been shown to increase collagen synthesis leading to plaque stabilization by reducing the expression of Arginase-2 (ARG2) in endothelial cells and nitric oxide synthase 2 (NOS2) in macrophages, while increasing the expression of TGF-β1 and ARG1 [52].

Similar to AT-RvD1, MaR1 has also been found to induce Nrf2, increasing cytoplasmic HMOX1, thus reducing the levels of ROS and improved pulmonary ischemia/reperfusion injury [39].

While these studies shed light on SPM (LXA4, AT-RvD1, and MaR1)-Nrf2 relationship in increasing antioxidative proteins within pulmonary physiology, there is still debate on the overall cardioprotective effects of Nrf2, with studies showing that mice with Nrf2 −/−developed less atherosclerosis [58] and HMOX1 was seen highest within human plaques with characteristics of high instability [59]. Roles of Nrf2 in lipid metabolism [58], in reduction of scavenger receptor CD36 resulting in reduced foam cell formation [60], and in NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome induction by cholesterol crystals within the atherosclerotic plaque have been attributed to these counterintuitive results of increased atherosclerosis with complete absence of Nrf2 expression [61].
