Abstract 1155: Anti-Atherosclerotic Properties of the Angiotensin II Receptor Antagonist Telmisartan in Advanced Atherosclerosis
Atherosclerosis is an inflammatory disease which may lead to acute coronary syndromes. Advanced atherosclerotic plaques are characterized by the presence of a large necrotic core, which is separated from the lumen by a thin fibrous cap. Inflammatory mechanisms are involved in processes leading to plaque rupture. Clinical studies have demonstrated that the inhibition of the renin-angiotensin system (RAS) by either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor type 1 (AT1)-antagonist reduces cardiovascular events. The objective of this study was to evaluate the different mechanisms of the AT1-antagonist Telmisartan in comparison to the ACE-inhibitor Ramipril on already established advanced atherosclerotic lesions in older ApolipoproteinE deficient mice. Seven month old ApolipoproteinE deficient mice (n=60) exhibiting advanced atherosclerotic lesions within the innominate artery were fed a chow diet supplemented with the ACE-inhibitor Ramipril (5 mg/kg/day, n=20) or with the AT1-antagonist Telmisartan (40 mg/kg/day, n+20) for 16 weeks. 20 mice received regular chow diet. Mice receiving Telmisartan had a 40% reduction and mice receiving Ramipril had a 20% reduction in cross sectional area of atherosclerotic lesions in the innominate artery compared to controls. Signs of plaque instability such as intra-plaque hemorrhage and large necrotic cores were less frequent in mice receiving Telmisartan. Furthermore, Telmisartan treated mice had lower activation of AP-1 and NFκB in the aorta as demonstrated with electro mobility shift assays. In vitro studies in mouse macrophages demonstrated enhanced activation of PPARgamma by Telmisartan as demonstrated by RT-PCR and luciferase reporter contructs of the PPARgamma promoter. Target genes of PPARgamma, such as inducible nitric oxide synthase, also showed decreased lipopolysaccharide induced expression after pretreatment with Telmisartan. These data suggest that chronic inhibition of the RAS by the AT1−antagonist Telmisartan prevails in reducing advanced atherosclerosis and promoting plaque stability possibly through the inhibition of the activation of the proinflam-matory transcription factors AP-1 and NFκB and through the activation of PPARgamma.