Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators

Atherosclerosis is now recognized as an inflammatory disease involving the vascular wall. Recent results indicate that acute inflammation does not simply passively resolve as previously assumed but is actively terminated by a homeostatic process that is governed by specific lipid-derived mediators initiated by lipoxygenases. Experiments with animals and humans support a proinflammatory role for the 5-lipoxygenase system. In contrast, results from animal experiments show a range of responses with the 12/15-lipoxygenase pathways in atherosclerosis. To date, the only two clinical epidemiology human studies both support an antiatherogenic role for 12/15-lipoxygenase downstream actions. We tested the hypothesis that atherosclerosis results from a failure in the resolution of local inflammation by analyzing apolipoprotein E-deficient mice with 1) global leukocyte 12/15-lipoxygenase deficiency, 2) normal enzyme expression, or 3) macrophage-specific 12/15-lipoxygenase overexpression. Results from these indicate that 12/15-lipoxygenase expression protects mice against atherosclerosis via its role in the local biosynthesis of lipid mediators, including lipoxin A4, resolvin D1, and protectin D1. These mediators exert potent agonist actions on macrophages and vascular endothelial cells that can control the magnitude of the local inflammatory response. Taken together, these findings suggest that a failure of local endogenous resolution mechanisms may underlie the unremitting inflammation that fuels atherosclerosis.—Merched, A. J., Ko, K., Gotlinger, K. H., Serhan, C. N. Chan, L. Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators

Targeting Lipid Metabolism in Liver Cancer

International audienceCancer cells are highly dependent on different metabolic pathways for sustaining their survival, growth, and proliferation. Lipid metabolism not only provides the energetic needs of the cells but also provides the raw material for cellular growth and the signaling molecules for many oncogenic pathways. Mainly processed in the liver, lipids play an essential role in the physiology of this organ and in the pathological progression of many diseases such as metabolic syndrome and hepatocellular carcinoma (HCC). The progression of HCC is associated with inflammation and complex metabolic reprogramming, and its prognosis remains poor because of the lack of effective therapies despite many years of dedicated research. Defects in hepatic lipid metabolism induce abnormal gene expression and rewire many cellular pathways involved in oncogenesis and metastasis, implying that interfering with lipid metabolism within the tumor and the surrounding microenvironment may be a novel therapeutic approach for treating liver cancer patients. Therefore, this review focuses on the latest advances in drugs targeting lipid metabolism and leading to promising outcomes in preclinical studies and some ongoing clinical trials

Faseb J

Higher cardiovascular morbidity in patients with a wide range of autoimmune diseases highlights the importance of autoimmunity in promoting atherosclerosis. Our purpose was to investigate the mechanisms of accelerated atherosclerosis and identified vascular autoantigens targeted by autoimmunity. We created a mouse model of autoimmunity-associated atherosclerosis by transplanting bone marrow (BM) from FcγRIIB knockout (FcRIIB-/-) mice into LDL receptor knockout (LDLR-/-) mice. We characterized the cellular and molecular mechanisms of atherogenesis and identified specific aortic autoantigens using serologic proteomic studies. En face lesion area analysis showed more aggressive atherosclerosis in autoimmune mice compared with control mice (0.64 ± 0.12 mm2 vs. 0.32 ± 0.05 mm2; P \textless 0.05, respectively). At the cellular level, FcRIIB-/- macrophages showed significant reduction (46-72%) in phagocytic capabilities. Proteomic analysis revealed circulating autoantibodies in autoimmune mice that targeted 25 atherosclerotic lesion proteins, including essential components of adhesion complex, cytoskeleton, and extracellular matrix (ECM), and proteins involved in critical functions and pathways. Microscopic examination of atherosclerotic plaques revealed essential colocalization of autoantibodies with endothelial cells (ECs), their adherence to basement membranes, the internal elastica lamina, and necrotic cores. The new vascular autoimmunosome may be a useful target for diagnostic and immunotherapeutic interventions in autoimmunity-associated diseases that have accelerated atherosclerosi