Institut für Pharmakologie, Universitätsklinikum Essen, Universität Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.
Basic Res Cardiol. 2010 Jan;105(1):29-38. doi: 10.1007/s00395-009-0051-1. Epub 2009 Aug 23.
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.
核心蛋白聚糖（Biglycan）是一种富含亮氨酸的小蛋白聚糖，在早期动脉粥样硬化过程中，它在新生内膜中的积累先于脂质的保留和巨噬细胞的积累。因此，核心蛋白聚糖被认为是一种促动脉粥样硬化的蛋白聚糖，可能在动脉粥样硬化的发生中发挥关键作用。另一方面，核心蛋白聚糖部分确保了稳定的胶原网络的建立。本研究的目的是确定替米沙坦是否会影响加速动脉粥样硬化小鼠模型中核心蛋白聚糖的积累，以及胶原基质是否会受到影响。给予载脂蛋白 E 基因敲除（ApoE(-/-)）小鼠西方饮食，并进行慢性（12 周）替米沙坦（10mg/kg）或肼屈嗪（500mg/L 饮用水）治疗，通过尾套测压法测定收缩压。处死动物，分析主动脉斑块评分、斑块形态和细胞外基质以及主动脉根部的细胞斑块组成。此外，还分析了主动脉中核心蛋白聚糖和参与胶原交联的酶的表达。替米沙坦和肼屈嗪均能显著降低收缩压，但替米沙坦可显著降低主动脉和主动脉根部核心蛋白聚糖的积累，但肼屈嗪无此作用。替米沙坦对 picrosirius 红染色、mac2 和 alpha-SM-actin 分析的胶原和胶原纤维密度、巨噬细胞和 SMCs 数量没有影响，而肼屈嗪也没有影响。此外，与接受肼屈嗪治疗和未治疗对照组的小鼠相比，替米沙坦抑制了主动脉斑块评分和主动脉根部斑块大小。本研究表明，替米沙坦可降低核心蛋白聚糖的积累，抑制动脉粥样硬化，独立于降压作用，且不影响胶原性斑块基质。因此，核心蛋白聚糖是替米沙坦的一种多效性靶点，可能有助于这种 AT1 拮抗剂的抗动脉粥样硬化作用。
