Resolvins, Specialized Proresolving Lipid Mediators, and Their Potential Roles in Metabolic Diseases

Inflammation is associated with the development of diseases characterized by altered nutrient metabolism. Although an acute inflammatory response is host-protective and normally self-limited, chronic low-grade inflammation associated with metabolic diseases is sustained and detrimental. The resolution of inflammation involves the termination of neutrophil recruitment, counterregulation of proinflammatory mediators, stimulation of macrophage-mediated clearance, and tissue remodeling. Specialized proresolving lipid mediators (SPMs)–resolvins, protectins, and maresins–are novel autacoids that resolve inflammation, protect organs, and stimulate tissue regeneration. Here, we review evidence that the failure of resolution programs contributes to metabolic diseases and that SPMs may play pivotal roles in their resolution

Regulation and Maintenance of Vascular Tone and Patency in Cardiovascular Health and Disease

License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Despite numerous advances in health care practices, cardiovascular disease still remains the leading cause of morbidity and mortality worldwide. Perhaps the most important consequence of cardiovascular disease is the interruption of blood flow to organs such as the heart and brain, resulting in the clinical presentation of a heart attack or stroke. As such, the regulation of vascular tone and the maintenance of vascular patency are vital for the preservation of cardiovascular health. Central to this process is the vascular endothelium. The endothelium is vital for the regulation of vascular tone and the maintenance of vascular homeostasis, as it releases factors such as nitric oxide, hydrogen sulfide, endothelialdependent hyperpolarizing factor, and prostacyclin tha

Metabolic remodeling of white adipose tissue in obesity

Adipose tissue metabolism is a critical regulator of adiposity and whole body energy expenditure; however, metabolic changes that occur in white adipose tissue (WAT) with obesity remain unclear. The purpose of this study was to understand the metabolic and bioenergetic changes occurring in WAT with obesity. Wild-type (C57BL/6J) mice fed a high-fat diet (HFD) showed significant increases in whole body adiposity, had significantly lower V̇o2, V̇co2, and respiratory exchange ratios, and demonstrated worsened glucose and insulin tolerance compared with low-fat-fed mice. Metabolomic analysis of WAT showed marked changes in lipid, amino acid, carbohydrate, nucleotide, and energy metabolism. Tissue levels of succinate and malate were elevated, and metabolites that could enter the Krebs cycle via anaplerosis were mostly diminished in high-fat-fed mice, suggesting altered mitochondrial metabolism. Despite no change in basal oxygen consumption or mitochondrial DNA abundance, citrate synthase activity was decreased by more than 50%, and responses to FCCP were increased in WAT from mice fed a high-fat diet. Moreover, Pgc1a was downregulated and Cox7a1 upregulated after 6 wk of HFD. After 12 wk of high-fat diet, the abundance of several proteins in the mitochondrial respiratory chain or matrix was diminished. These changes were accompanied by increased Parkin and Pink1, decreased p62 and LC3-I, and ultrastructural changes suggestive of autophagy and mitochondrial remodeling. These studies demonstrate coordinated restructuring of metabolism and autophagy that could contribute to the hypertrophy and whitening of adipose tissue in obesity

An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques

Chronic unresolved inflammation plays a causal role in the development of advanced atherosclerosis, but the mechanisms that prevent resolution in atherosclerosis remain unclear. Here, we use targeted mass spectrometry to identify specialized pro-resolving lipid mediators (SPM) in histologically-defined stable and vulnerable regions of human carotid atherosclerotic plaques. The levels of SPMs, particularly resolvin D1 (RvD1), and the ratio of SPMs to pro-inflammatory leukotriene B4 (LTB₄), are significantly decreased in the vulnerable regions. SPMs are also decreased in advanced plaques of fat-fed Ldlr⁻/⁻ mice. Administration of RvD1 to these mice during plaque progression restores the RvD1:LTB₄ ratio to that of less advanced lesions and promotes plaque stability, including decreased lesional oxidative stress and necrosis, improved lesional efferocytosis, and thicker fibrous caps. These findings provide molecular support for the concept that defective inflammation resolution contributes to the formation of clinically dangerous plaques and offer a mechanistic rationale for SPM therapy to promote plaque stability

A Comparison of Copper Abundances in Globular Cluster and Halo Field Giant Stars

We derive [Cu/Fe] for 117 giant stars in ten globular clusters (M3, M4, M5, M10, M13, M15, M71, NGC 7006, NCG 288, and NGC 362) and find that globular cluster Cu abundances appear to follow [Cu/Fe] trends found in the field. This result is interesting in light of recent work which indicates that the globular cluster Omega Centauri shows no trend in [Cu/Fe] with [Fe/H] over the abundance range -2.0 <[Fe/H]< -0.8. Of particular interest are the two clusters M4 and M5. While at a similar metallicity ([Fe/H] ~- 1.2), they differ greatly in some elemental abundances: M4 is largely overabundant in Si, Ba, and La compared to M5. We find that it is also overabundant in Cu with respect to M5, though this overabundance is in accord with [Cu/Fe] ratios found in the field.Comment: 39 pages, 7 figures, to appear in April 2003 A

Varga et al.: Macrophage PPARγ, a Lipid Activated Transcription Factor Controls the Growth Factor GDF3 and Skeletal Muscle Regeneration Immunity. 2016 Nov 15;45(5):1038-1051. doi: 10.1016/j.immuni.2016.10.016.

Tissue regeneration requires inflammatory and reparatory activity of macrophages. Macrophages detect and eliminate the damaged tissue and subsequently promote regeneration. This dichotomy requires the switch of effector functions of macrophages coordinated with other cell types inside the injured tissue. The gene regulatory events supporting the sensory and effector functions of macrophages involved in tissue repair are not well understood. Here we show that the lipid activated transcription factor, PPARγ, is required for proper skeletal muscle regeneration, acting in repair macrophages. PPARγ controls the expression of the transforming growth factor-β (TGF-β) family member, GDF3, which in turn regulates the restoration of skeletal muscle integrity by promoting muscle progenitor cell fusion. This work establishes PPARγ as a required metabolic sensor and transcriptional regulator of repair macrophages. Moreover, this work also establishes GDF3 as a secreted extrinsic effector protein acting on myoblasts and serving as an exclusively macrophage-derived regeneration factor in tissue repair

Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions

The endogenous cellular and molecular mechanisms that control acute inflammation and its resolution are of wide interest. Using self-resolving inflammatory exudates and lipidomics, we have identified a new pathway involving biosynthesis of potent antiinflammatory and proresolving mediators from the essential fatty acid docosahexaenoic acid (DHA) by macrophages (MΦs). During the resolution of mouse peritonitis, exudates accumulated both 17-hydroxydocosahexaenoic acid, a known marker of 17S-D series resolvin (Rv) and protectin biosynthesis, and 14S-hydroxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid from endogenous DHA. Addition of either DHA or 14S-hydroperoxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid to activated MΦs converted these substrates to novel dihydroxy-containing products that possessed potent antiinflammatory and proresolving activity with a potency similar to resolvin E1, 5S,12R,18R-trihydroxyeicosa-6Z,8E,10E,14Z,16E-pentaenoic acid, and protectin D1, 10R,17S-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid. Stable isotope incorporation, intermediate trapping, and characterization of physical and biological properties of the products demonstrated a novel 14-lipoxygenase pathway, generating bioactive 7,14-dihydroxydocosa-4Z,8,10,12,16Z,19Z-hexaenoic acid, coined MΦ mediator in resolving inflammation (maresin), which enhances resolution. These findings suggest that maresins and this new metabolome may be involved in some of the beneficial actions of DHA and MΦs in tissue homeostasis, inflammation resolution, wound healing, and host defense

Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis

National Institutes of Health grants GM-38765 and P50-DE016191 (C.N.S.), Welcome Trust Programme grant 086867/Z/08/Z (R.J.F. and M.P.) and Project grant 085903/Z/08 (R.J.F.) and Arthritis Research Campaign UK fellowships 18445 and 18103 (to L.V.N. and D.C., respectively). M.S. received a National Research Service Award from the NHLBI (HL087526)