Anti-atherosclerotic properties of telmisartan in advanced atherosclerotic lesions in apolipoprotein E deficient mice.
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 (AT(1))-antagonist reduces cardiovascular disease. The objective of this study was to evaluate underlying mechanisms of the AT(1)-antagonist telmisartan in comparison to the ACE-inhibitor ramipril on advanced atherosclerotic lesions. Thirty-two-week-old apolipoprotein E deficient mice (n=60) exhibiting advanced atherosclerotic lesions were fed a chow diet supplemented with ramipril or telmisartan for 16 weeks. Twenty mice received a standard diet. Mice receiving telmisartan had a 38% and mice receiving ramipril had a 18% reduction in progression of atherosclerotic lesion size within the innominate artery. Signs of plaque instability such as frequency of intra-plaque hemorrhage and size of the necrotic cores were reduced in mice receiving telmisartan. Furthermore, telmisartan-treated mice had fewer macrophages and reduced expression of early growth response gene-1 (Egr-1) within the lesions. Electrophoretic mobility shift assays revealed reduced DNA-binding activity of nuclear factor kappaB (NFkappaB) in the aorta of telmisartan-treated mice. In vitro studies in mouse macrophages demonstrated enhanced promoter activation of the nuclear transcription factor peroxisome proliferators-activated receptor gamma (PPARgamma). Target genes of PPARgamma, such as inducible nitric oxide synthase, NFkappaB and Egr-1, showed reduced activity after telmisartan pretreatment. These data suggest that chronic inhibition of the RAS by telmisartan prevails in reducing advanced atherosclerosis and promoting plaque stability over ramipril, possibly through the reduced activity of the pro-inflammatory transcription factors NFkappaB and Egr-1 and through the activation of PPARgamma.
Blessing
Erwin
E
Medizinische Klinik III, Universität Heidelberg, Heidelberg, Germany.
Preusch
Michael
M
Kranzhöfer
Roger
R
Kinscherf
Ralf
R
Marx
Nikolaus
N
Rosenfeld
Michael E
ME
Isermann
Berend
B
Weber
Christian M
CM
Kreuzer
Jörg
J
Gräfe
Julia
J
Katus
Hugo A
HA
Bea
Florian
F
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics*; D050197:Atherosclerosis / Q000188:drug therapy* / Q000473:pathology; D001562:Benzimidazoles / Q000494:pharmacology*; D001565:Benzoates / Q000494:pharmacology*; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D007249:Inflammation; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects; D000077333:Telmisartan
D047228:Angiotensin II Type 1 Receptor Blockers; D001057:Apolipoproteins E; D001562:Benzimidazoles; D001565:Benzoates; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D016328:NF-kappa B; D047495:PPAR gamma; D052247:Nitric Oxide Synthase Type II; D000077333:Telmisartan