Inhibition of endothelial nitric oxide synthase (eNOS) accelerates atherosclerosis in ApoE-null mice by impairing the balance between angiotensin II (AII) and NO. Our previous data suggested a role for PPARα in the deleterious effect of the renin-angiotensin system (RAS). We tested the hypothesis that ApoE-null mice lacking PPARα (DKO mice) would be resistant to the proatherogenic effect of NOS inhibition. DKO mice fed a Western diet were immune to the 23% worsening in aortic sinus plaque area seen in the ApoE-null animals under 12 weeks of NOS inhibition with a subpressor dose of L-NAME, . This was accompanied by a doubling of reactive oxygen species (ROS-) generating aortic NADPH oxidase activity (a target of AII, which paralleled Nox1 expression) and by a 10-fold excess of the proatherogenic iNOS, . L-NAME also caused a doubling of aortic renin and angiotensinogen mRNA level in the ApoE-null mice but not in the DKO, and it upregulated eNOS in the DKO mice only. These data suggest that, in the ApoE-null mouse, PPARα contributes to the proatherogenic effect of unopposed RAS/AII action induced by L-NAME, an effect which is associated with Nox1 and iNOS induction, and is independent of blood pressure and serum lipids. 1. Introduction Expressed in all the cellular components of the vascular wall, and present in the atherosclerotic plaque, the precise role of the peroxisome proliferator-activated receptor alpha (PPARα) in atherogenesis is still controversial. Its known effect on lipoprotein metabolism, and mostly surrogate endpoints derived from animal studies, helped shape the view that its activation confers protection against atherosclerosis (for review [1]). Large clinical trials designed to assess the potential of fibrates to reduce the rate of cardiovascular endpoints have, however, reached mixed results, suggesting that benefit may be restricted to subsets of subjects with defined lipoprotein abnormalities [2–4]. We previously reported that ApoE-null mice lacking PPARα were resistant to diet-induced atherosclerosis, despite exhibiting the worsened lipid profile expected from the absence of PPARα. In addition, the double knockout mice had also a somewhat lower blood pressure [5]. Although by itself this reduction could not explain the protection from atherosclerosis, it suggested that PPARα could affect a system central to both atherogenesis and blood pressure regulation. In this respect, a natural candidate is the renin-angiotensin system (RAS). We subsequently showed that ablation of PPARα totally abolished hypertension and greatly reduced
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