sphingosine-1-phosphate and Aortic-Aneurysm--Abdominal

Currently, the relationship between circulating lipids and abdominal aortic aneurysm (AAA) is unclear. We conducted a lipidomic analysis to identify serum lipids associated with AAA presence. Secondary analyses assessed the ability of models incorporating lipidomic features to improve stratification of patient groups with and without AAA beyond traditional risk factors.. Serum lipids were profiled via liquid chromatography tandem mass spectrometry analysis of serum from 161 patients with AAA and 168 controls with peripheral artery disease. Binary logistic regression was used to identify AAA-associated lipids. Classification models were created based on a combination of (1) traditional risk factors only or (2) lipidomic features and traditional risk factors. Model performance was assessed using receiver operator characteristic curves. Three diacylglycerols and 7 triacylglycerols were associated with AAA. Combining lipidomic features with traditional risk factors significantly improved stratification of AAA and peripheral artery disease groups when compared with traditional risk factors alone (mean area under the receiver operator characteristic curve [95% confidence interval], 0.760 [0.756-0.763] and 0.719 [0.716-0.723], respectively; P<0.05).. A group of linoleic acid containing triacylglycerols and diacylglycerols were significantly associated with AAA presence. Inclusion of lipidomic features in multivariate analyses significantly improved prediction of AAA presence when compared with traditional risk factors alone.

Topics: Aged; Aortic Aneurysm, Abdominal; Area Under Curve; Chromatography, High Pressure Liquid; Diglycerides; Female; Humans; Lipids; Logistic Models; Lysophospholipids; Male; Middle Aged; Odds Ratio; Peripheral Arterial Disease; Risk Factors; ROC Curve; Sphingosine; Tandem Mass Spectrometry; Triglycerides

There are currently no acceptable treatments to limit progression of abdominal aortic aneurysm (AAA). Increased serum concentrations of high-density lipoprotein (HDL) are associated with reduced risk of developing an AAA. The present study aimed to assess the effects of fenofibrate on aortic dilatation in a mouse model of AAA. Male low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice were maintained on a high-fat diet for 3 weeks followed by 6 weeks of oral administration of vehicle or fenofibrate. From 14 to 18 weeks of age, all mice were infused with angiotensin II (AngII). At 18 weeks of age, blood and aortas were collected for assessment of serum lipoproteins, aortic pathology, aortic Akt1 and endothelial nitric oxide synthase (eNOS) activities, immune cell infiltration, eNOS and inducible NOS (iNOS) expression, sphingosine 1 phosphate (S1P) receptor status, and apoptosis. Mice receiving fenofibrate had reduced suprarenal aortic diameter, reduced aortic arch Sudan IV staining, higher serum HDL levels, increased serum S1P concentrations, and increased aortic Akt1 and eNOS activities compared with control mice. Macrophages, T lymphocytes, and apoptotic cells were less evident and eNOS, iNOS, and S1P receptors 1 and 3 were up-regulated in aortas from mice receiving fenofibrate. The present findings suggest that fenofibrate antagonizes AngII-induced AAA and atherosclerosis by up-regulating serum HDL and S1P levels, with associated activation of NO-producing enzymes and reduction of aortic inflammation.

Topics: Angiotensin II; Animals; Aorta; Aorta, Thoracic; Aortic Aneurysm, Abdominal; Apoptosis; Azo Compounds; Dilatation, Pathologic; Disease Models, Animal; Disease Progression; Endothelial Cells; Fenofibrate; Inflammation; Kidney; Lipoproteins, HDL; Lysophospholipids; Male; Mice; Mice, Inbred C57BL; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Proto-Oncogene Proteins c-akt; Receptors, Lysosphingolipid; Sphingosine; Treatment Outcome; Up-Regulation