Advertisement

Increased atherosclerosis following treatment with a dual PPAR agonist in the ApoE knockout mouse

      Abstract

      Objective

      Recent reports have suggested that dual peroxisome proliferator-activated receptor (PPAR) α/γ agonists are associated with adverse cardiovascular events. This study aimed to investigate the actions of the non-thiazolidinedione PPARα/γ agonist, compound 3q, on plaque development in the apolipoprotein E knockout (apoE KO) mouse, a recognised model of accelerated plaque development.

      Methods

      Six-week-old male apoE KO mice were randomised to receive the dual PPARα/γ agonist, compound 3q (3 mg/kg/day), the PPARγ agonist, rosiglitazone (20 mg/kg/day), the PPARα agonist, gemfibrozil (100 mg/kg/day) by gavage or no treatment for 20 weeks (n = 12/group).

      Results

      Gemfibrozil and rosiglitazone significantly reduced lesion area. However, compound 3q was associated with a three-fold increase in total plaque area (versus control p < 0.001). This was associated with an upregulation of markers of plaque instability including vascular cell adhesion molecule-1 (3.5-fold, p < 0.001), P-selectin (3.4-fold, p < 0.001) monocyte chemoattractant protein-1 (3.4-fold; p < 0.001) as well as the scavenger receptor, CD36 (2-fold, p < 0.01). These disparate effects were observed with the dual PPAR agonist despite lowering LDL cholesterol and improving insulin sensitivity to a similar extent to PPARα and γ agonists used individually.

      Conclusion

      The finding of increased atherogenesis following a dual PPARα/γ agonist is consistent with recent clinical findings. These data provide an important framework for further exploring the potential utility and safety of combinatorial approaches.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Spiegelman B.M.
        PPAR-gamma: adipogenic regulator and thiazolidinedione receptor.
        Diabetes. 1998; 47: 507-514
        • Guan Y.
        Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome.
        J Am Soc Nephrol. 2004; 15: 2801-2815
        • Lohray B.B.
        • Lohray V.B.
        • Bajji A.C.
        • et al.
        (−)3-[4-[2-(Phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxypropanoic acid [(−)DRF 2725]: a dual PPAR agonist with potent antihyperglycemic and lipid modulating activity.
        J Med Chem. 2001; 44: 2675-2678
        • Nissen S.E.
        • Wolski K.
        • Topol E.J.
        Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus.
        JAMA. 2005; 294: 2581-2586
        • Calkin A.C.
        • Forbes J.M.
        • Smith C.M.
        • et al.
        Rosiglitazone attenuates atherosclerosis in a model of insulin insufficiency independent of its metabolic effects.
        Arterioscler Thromb Vasc Biol. 2005; 25: 1903-1909
        • Calkin A.C.
        • Cooper M.E.
        • Jandeleit-Dahm K.A.
        • Allen T.J.
        Gemfibrozil decreases atherosclerosis in experimental diabetes in association with a reduction in oxidative stress and inflammation.
        Diabetologia. 2006; 49: 766-774
        • Moghadasian M.H.
        • McManus B.M.
        • Nguyen L.B.
        • et al.
        Pathophysiology of apolipoprotein E deficiency in mice: relevance to apo E-related disorders in humans.
        FASEB J. 2001; 15: 2623-2630
        • Wen M.
        • Segerer S.
        • Dantas M.
        • et al.
        Renal injury in apolipoprotein E-deficient mice.
        Lab Invest. 2002; 82: 999-1006
        • Cefalu W.T.
        • Wang Z.Q.
        • Bell-Farrow A.
        • Kiger F.D.
        • Izlar C.
        Glycohemoglobin measured by automated affinity HPLC correlates with both short-term and long-term antecedent glycemia.
        Clin Chem. 1994; 40: 1317-1321
        • Candido R.
        • Jandeleit-Dahm K.A.
        • Cao Z.
        • et al.
        Prevention of accelerated atherosclerosis by angiotensin-converting enzyme inhibition in diabetic apolipoprotein E-deficient mice.
        Circulation. 2002; 106: 246-253
        • Tordjman K.
        • Bernal-Mizrachi C.
        • Zemany L.
        • et al.
        PPARalpha deficiency reduces insulin resistance and atherosclerosis in apoE-null mice.
        J Clin Invest. 2001; 107: 1025-1034
        • Tian J.
        • Pei H.
        • James J.C.
        • et al.
        Circulating adhesion molecules in apoE-deficient mouse strains with different atherosclerosis susceptibility.
        Biochem Biophys Res Commun. 2005; 329: 1102-1107
      1. Nestel P, Fujii A, Allen T. The cis-9,trans-11 isomer of conjugated linoleic acid (CLA) lowers plasma triglyceride and raises HDL cholesterol concentrations but does not suppress aortic atherosclerosis in diabetic apoE-deficient mice. Atherosclerosis; 2006.

        • Ko K.W.
        • Paul A.
        • Ma K.
        • Li L.
        • Chan L.
        Endothelial lipase modulates HDL but has no effect on atherosclerosis development in apoE−/− and LDLR−/− mice.
        J Lipid Res. 2005; 46: 2586-2594
        • Bentzon J.F.
        • Skovenborg E.
        • Hansen C.
        • et al.
        Red wine does not reduce mature atherosclerosis in apolipoprotein E-deficient mice.
        Circulation. 2001; 103: 1681-1687
        • Gonzalez F.J.
        Recent update on the PPAR alpha-null mouse.
        Biochimie. 1997; 79: 139-144
        • Chawla A.
        • Barak Y.
        • Nagy L.
        • et al.
        PPAR-gamma dependent and independent effects on macrophage-gene expression in lipid metabolism and inflammation.
        Nat Med. 2001; 7: 48-52
        • Liu H.B.
        • Hu Y.S.
        • Medcalf R.L.
        • Simpson R.W.
        • Dear A.E.
        Thiazolidinediones inhibit TNFalpha induction of PAI-1 independent of PPARgamma activation.
        Biochem Biophys Res Commun. 2005; 334: 30-37
        • Moulin D.
        • Bianchi A.
        • Boyault S.
        • et al.
        Rosiglitazone induces interleukin-1 receptor antagonist in interleukin-1beta-stimulated rat synovial fibroblasts via a peroxisome proliferator-activated receptor beta/delta-dependent mechanism.
        Arthritis Rheum. 2005; 52: 759-769
        • Hattori Y.
        • Hattori S.
        • Kasai K.
        Troglitazone upregulates nitric oxide synthesis in vascular smooth muscle cells.
        Hypertension. 1999; 33: 943-948