Long-term treatment with the AT1-receptor antagonist telmisartan inhibits biglycan accumulation in murine atherosclerosis.
Accumulation of biglycan, a small leucine-rich proteoglycan, in the neointima precedes the retention of lipids and accumulation of macrophages during early atherosclerosis. Biglycan is therefore considered a pro-atherogenic proteoglycan that might play a key role in atherogenesis. On the other hand biglycan ensures in part establishment of stable collagen networks. Aim of the present study was to determine whether telmisartan affects biglycan accumulation in a murine model of accelerated atherosclerosis and whether collagen matrix is affected. ApoE(-/-)-mice on Western diet were chronically (12 weeks) treated either with telmisartan (10 mg/kg) or hydralazine (500 mg/l drinking water) and systolic arterial blood pressure was determined by tail cuff plethysmography. Animals were killed and aortic plaque score, plaque morphology and extracellular matrix as well as cellular plaque composition were analyzed at the aortic root. Furthermore, expression of biglycan and enzymes involved in collagen cross-linking were analyzed in the aorta. Telmisartan and hydralazine lowered systolic arterial blood pressure to the same extent. Biglycan accumulation in the aorta and the aortic root was significantly reduced by telmisartan but not by hydralazine. The amount of collagen and collagen fibril density, macrophages and SMCs was not affected by either treatment as determined by analysis of picrosirius red staining, mac2 and alpha-SM-actin. Furthermore, telmisartan inhibited aortic plaque score and aortic root plaque size compared to mice receiving hydralazine and untreated controls. The current study shows that telmisartan reduces biglycan accumulation and inhibits atherosclerosis independently of blood pressure lowering and without affecting the collagenous plaque matrix. Thus, biglycan is a pleiotropic target of telmisartan that might contribute to the anti-atherogenic effects of this AT1-antagonist.
Nagy
Nadine
N
Institut für Pharmakologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.
Melchior-Becker
Ariane
A
Fischer
Jens W
JW
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001011:Aorta / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D058578:Biglycan; D001794:Blood Pressure / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism*; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011509:Proteoglycans / Q000378:metabolism*; D000077333:Telmisartan
D047228:Angiotensin II Type 1 Receptor Blockers; D001057:Apolipoproteins E; D001562:Benzimidazoles; D001565:Benzoates; C546885:Bgn protein, mouse; D058578:Biglycan; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D003094:Collagen; D000077333:Telmisartan