Dual PPARalpha/gamma agonist tesaglitazar reduces atherosclerosis in insulin-resistant and hypercholesterolemic ApoE*3Leiden mice.
OBJECTIVE
We investigated whether the dual PPARalpha/gamma agonist tesaglitazar has anti-atherogenic effects in ApoE*3Leiden mice with reduced insulin sensitivity.


RESULTS
ApoE*3Leiden transgenic mice were fed a high-fat (HF) insulin-resistance-inducing diet. One group received a high-cholesterol (HC) supplement (1% wt/wt; HC group). A second group received the same HC supplement along with tesaglitazar (T) 0.5 micromol/kg diet (T group). A third (control) group received a low-cholesterol (LC) supplement (0.1% wt/wt; LC group). Tesaglitazar decreased plasma cholesterol by 20% compared with the HC group; cholesterol levels were similar in the T and LC groups. Compared with the HC group, tesaglitazar caused a 92% reduction in atherosclerosis, whereas a 56% reduction was seen in the cholesterol-matched LC group. Furthermore, tesaglitazar treatment significantly reduced lesion number beyond that expected from cholesterol lowering and induced a shift to less severe lesions. Concomitantly, tesaglitazar reduced macrophage-rich and collagen areas. In addition, tesaglitazar reduced inflammatory markers, including plasma SAA levels, the number of adhering monocytes, and nuclear factor kappaB-activity in the vessel wall.


CONCLUSIONS
Tesaglitazar has anti-atherosclerotic effects in the mouse model that go beyond plasma cholesterol lowering, possibly caused by a combination of altered lipoprotein profiles and anti-inflammatory vascular effects.
Zadelaar
A Susanne M
AS
Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands.
Boesten
Lianne S M
LS
Jukema
J Wouter
JW
van Vlijmen
Bart J M
BJ
Kooistra
Teake
T
Emeis
Jef J
JJ
Lundholm
Erik
E
Camejo
German
G
Havekes
Louis M
LM
D000476:Alkanesulfonates / Q000494:pharmacology*; D000818:Animals; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000378:metabolism*; D050197:Atherosclerosis / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology; D015415:Biomarkers / Q000097:blood; D001808:Blood Vessels / Q000473:pathology; D002448:Cell Adhesion; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000008:administration & dosage; D003094:Collagen / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D005260:Female; D006937:Hypercholesterolemia / Q000097:blood / Q000150:complications / Q000503:physiopathology*; D007249:Inflammation / Q000097:blood; D007333:Insulin Resistance; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D010666:Phenylpropionates / Q000494:pharmacology*
D000476:Alkanesulfonates; D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D015415:Biomarkers; D002791:Cholesterol, Dietary; D004041:Dietary Fats; D008055:Lipids; D008074:Lipoproteins; D016328:NF-kappa B; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates; C052720:apolipoprotein E3 (Leidein); C501413:tesaglitazar; D003094:Collagen; D002784:Cholesterol