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.
Methods and 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.