Tesaglitazar, a dual peroxisome proliferator-activated receptor alpha/gamma agonist, reduces atherosclerosis in female low density lipoprotein receptor deficient mice.
OBJECTIVE
The transcription factors, peroxisome proliferator-activated receptors (PPAR) alpha (alpha) and gamma (gamma), which are involved in lipid and glucose homeostasis, also exert modulatory actions on vascular cells where they exhibit anti-inflammatory and anti-proliferative properties. Hence, PPAR agonists potentially can affect atherogenesis both via metabolic effects and direct effects on the vessel wall. We tested whether the dual PPAR-alpha/gamma agonist, tesaglitazar (TZ), would reduce atherosclerosis in a non-diabetic, atherosclerosis-prone mouse model, independent of effects on plasma lipids.


RESULTS
Low-density lipoprotein receptor deficient (LDLr-/-) mice were fed a Western type diet consisting of 21% butterfat and 0.15% cholesterol, with or without TZ 0.5 micromol/kg of diet, for 12 weeks. TZ reduced atherosclerosis in the female, but not male, LDLr-/- mice without affecting cholesterol and triglyceride levels, HDL binding to biglycan, or the inflammatory markers serum amyloid A (SAA) and serum amyloid P (SAP). TZ also decreased adiposity in both genders.


CONCLUSIONS
TZ reduced atherosclerosis in the female LDLr-/- mice via lipid-independent mechanisms, probably at least in part by direct actions on the vessels. The body weight changes in these mice are different from the effects of dual PPAR agonists seen in humans.
Chira
Ebele C
EC
Department of Medicine, University of Washington, Seattle, WA, USA.
McMillen
Timothy S
TS
Wang
Shari
S
Haw
Antonio
A
O'Brien
Kevin D
KD
Wight
Thomas N
TN
Chait
Alan
A
D000476:Alkanesulfonates / Q000494:pharmacology*; D000818:Animals; D050197:Atherosclerosis / Q000473:pathology*; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry; D005260:Female; D008055:Lipids / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015233:Models, Statistical; D047493:PPAR alpha / Q000819:agonists*; D047495:PPAR gamma / Q000819:agonists*; D010666:Phenylpropionates / Q000494:pharmacology*; D011973:Receptors, LDL / Q000235:genetics* / Q000502:physiology
D000476:Alkanesulfonates; D001786:Blood Glucose; D008055:Lipids; D047493:PPAR alpha; D047495:PPAR gamma; D010666:Phenylpropionates; D011973:Receptors, LDL; C501413:tesaglitazar; D002784:Cholesterol