Fenofibrate increases high-density lipoprotein and sphingosine 1 phosphate concentrations limiting abdominal aortic aneurysm progression in a mouse model

Krishna, Smriti M., Seto, Sai Wang, Moxon, Joseph V., Rush, Catherine, Walker, Philip J., Norman, Paul E. and Golledge, Jonathan (2012) Fenofibrate increases high-density lipoprotein and sphingosine 1 phosphate concentrations limiting abdominal aortic aneurysm progression in a mouse model. American Journal of Pathology, 181 2: 706-718.


Author Krishna, Smriti M.
Seto, Sai Wang
Moxon, Joseph V.
Rush, Catherine
Walker, Philip J.
Norman, Paul E.
Golledge, Jonathan
Title Fenofibrate increases high-density lipoprotein and sphingosine 1 phosphate concentrations limiting abdominal aortic aneurysm progression in a mouse model
Journal name American Journal of Pathology  (ERA 2012 Listed)    (ERA 2010 Rank A*)   Check publisher's open access policy
Publication date 2012-08
Sub-type Article
DOI 10.1016/j.ajpath.2012.04.015
Volume number 181
Issue number 2
ISSN 0002-9440; 1525-2191
Start page 706
End page 718
Total pages 13
Place of publication New York, NY, United States
Publisher Elsevier
Collection year 2013
Language eng
Formatted abstract 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.
Keyword E-deficient mice
Activated receptor-alpha
Nitric-oxide synthase
Randomized controlled-trial
Angiotensin-II
Endothelial-cells
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article
Collections: Official 2013 Collection
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