Fenofibrate increases high-density lipoprotein and sphingosine 1 phosphate concentrations limiting abdominal aortic aneurysm progression in a mouse model.
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.
Vascular Biology Unit, School of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia.
Smriti M
SM
Krishna
Sai Wang
SW
Seto
Joseph V
JV
Moxon
Catherine
C
Rush
Philip J
PJ
Walker
Paul E
PE
Norman
Jonathan
J
Golledge
D000804:Angiotensin II; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000097:blood* / Q000150:complications / Q000188:drug therapy / Q000473:pathology*; D017209:Apoptosis / Q000187:drug effects; D001391:Azo Compounds / Q000378:metabolism; D004108:Dilatation, Pathologic / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D011345:Fenofibrate / Q000494:pharmacology / Q000627:therapeutic use*; D007249:Inflammation / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D008075:Lipoproteins, HDL / Q000097:blood*; D008246:Lysophospholipids / Q000097:blood*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects
D001391:Azo Compounds; D008075:Lipoproteins, HDL; D008246:Lysophospholipids; D049349:Receptors, Lysosphingolipid; D000804:Angiotensin II; C060506:sphingosine 1-phosphate; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D051057:Proto-Oncogene Proteins c-akt; C009213:Scarlet Red; D013110:Sphingosine; D011345:Fenofibrate