Abstract-Peroxisome proliferator-activated receptor-␣ is widely distributed in the vasculature where it is believed to exert pleiotropic antiatherogenic effects. Its role in the regulation of blood pressure is still unresolved; however, some evidence suggests that it may affect the renin-angiotensin system. We investigated its role in angiotensin II-induced hypertension in the Tsukuba hypertensive mouse (THM). This is a model of hypertension and atherosclerosis because of high angiotensin II and aldosterone levels as a result of the transgenic expression of the entire human renin-angiotensin system. Making the THM animals deficient in Peroxisome proliferator-activated receptor-␣ (THM/ PPARKO) totally abolished hypertension and myocardial hypertrophy. This was accompanied by a reduction in plasma human active renin in THM/PPARKO mice compared with THM animals from 3525Ϯ128 mU/L to 1910Ϯ750 mU/L (PϽ0.05) and by a normalization of serum aldosterone (1.6Ϯ0.29 nmol/L versus 3.4Ϯ0.69 nmol/L; Pϭ0.003). In the THM/PPARKO mice, the extent of atherosclerosis at the aortic sinus after a 12-week period on an atherogenic diet was decreased by Ͼ80%. In addition, the spontaneous formation of foam cells from peritoneal macrophages, a blood pressure-independent event, was reduced by 92% in the THM/PPARKO mice, suggesting protection from the usual oxidative stress in these animals, possibly because of lower prevailing angiotensin II levels. Finally, chronic fenofibrate treatment further elevated blood pressure in THM animals but not in THM/PPARKO animals. Taken together, these data indicate that peroxisome proliferator-activated receptor-␣ may regulate the renin-angiotensin system. They raise the possibility that its activation may aggravate hypertension and hasten atherosclerosis in the context of an activated renin-angiotensin system. (Hypertension. 2007;50:945-951.)Key Words: PPAR␣ Ⅲ renin Ⅲ angiotensin Ⅲ hypertension Ⅲ atherosclerosis Ⅲ transgenic mice F irst identified and cloned from the liver as the nuclear receptor that mediates peroxisomal proliferation, proliferator-activated receptor (PPAR)-␣ has been found to be widely expressed in all of the cellular components of the vascular wall, where it is shown to exert pleiotropic antiatherogenic effects. Thus, in addition to its lipid-lowering effect, which mostly takes place in the liver, PPAR␣ is believed to impart direct protection in the vessel wall by intervening at essentially every level of the atherogenic process: inflammation, monocyte recruitment and adhesion, cholesterol transport, plaque formation, and thrombosis, mostly through downregulation of nuclear factor B and activator protein-1 (AP-1). [1][2][3] In contrast to the plethora of data regarding the atherogenic process, the role of PPAR␣ in the regulation of vascular tone and blood pressure is still unclear. Several studies conducted in different rat models of hypertension yielded inconsistent results. 4,5 In a previous study, we reported that the atherosclerosisprone apolipoprotein E (apoE)-null mice were pro...

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Aims:To determine whether low-dose calcitriol attenuates atherosclerosis in apoE-null mice and, if so, through which predominant mechanism. Methods: Starting at the age of 6 weeks, mice received intraperitoneal injections of either 0.25 ng/g body weight of calcitriol or the vehicle, every other day for 8 weeks.Results: Calcitriol treatment resulted in 35% reduction of atherosclerosis at the aortic sinus, and in a significant decrease in blood pressure. These effects were possibly mediated by downregulation of the renin-angiotensin system (RAS), as there was a 64% decrease in the aortic level of renin mRNA. None of the other components of the RAS or the prorenin receptor were affected by treatment. Lowdose calcitriol treatment did not modify the plasma level of monocyte chemoattractant protein-1, interferon γ, interleukin-4 and interleukin-10, which were similar in control and treated mice. Likewise, there was no difference in the percentage of splenic Foxp3 ＋ regulatory T cells. Calcitriol treatment resulted in an unfavorable metabolic profile (glucose and lipids), as determined after a limited fast, a difference that disappeared after food was withheld for a longer time. Conclusions: At a relatively low dosage, calcitriol attenuates the development of atherosclerosis in apoE-null mice, most probably by down regulation of RAS, and not through immunomodulation; however, even at this low dose, calcitriol appears to elevate calcium and to have potentially adverse metabolic effects. Exploring the potential antiatherogenic effects of non-calcemic and safer analogues is therefore warranted.