期刊
CIRCULATION
卷 124, 期 11, 页码 S168-S173出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCULATIONAHA.110.012187
关键词
aneurysm; aorta; pathology; remodeling; vessels
资金
- Howard Hughes Medical Institute Funding Source: Medline
Background-The sequelae of aortic root dilation are the lethal consequences of Marfan syndrome. The root dilation is attributable to an imbalance between deposition of matrix elements and metalloproteinases in the aortic medial layer as a result of excessive transforming growth factor-beta signaling. This study examined the efficacy and mechanism of statins in attenuating aortic root dilation in Marfan syndrome and compared effects to the other main proposed preventative agent, losartan. Methods and Results-Marfan mice heterozygous for a mutant allele encoding a cysteine substitution in fibrillin-1 (C1039G) were treated daily from 6 weeks old with pravastatin 0.5g/L or losartan 0.6 g/L. The end points of aortic root diameter (n = 25), aortic thickness, and architecture (n = 10), elastin volume (n = 5), dp/dtmax (maximal rate of change of pressure) (cardiac catheter; n = 20), and ultrastructural analysis with stereology (electron microscopy; n = 5) were examined. The aortic root diameters of untreated Marfan mice were significantly increased in comparison to normal mice (0.161 +/- 0.001 cm vs 0.252 +/- 0.004 cm; P < 0.01). Pravastatin (0.22 +/- 0.003 cm; P < 0.01) and losartan (0.221 +/- 0.004 cm; P < 0.01) produced a significant reduction in aortic root dilation. Both drugs also preserved elastin volume within the medial layer (pravastatin 0.23 +/- 0.02 and losartan 0.29 +/- 0.03 vs untreated Marfan 0.19 +/- 0.02; P = 0.01; normal mice 0.27 +/- 0.02). Ultrastructural analysis showed a reduction of rough endoplasmic reticulum in smooth muscle cells with pravastatin (0.022 +/- 0.004) and losartan (0.013 +/- 0.001) compared to untreated Marfan mice (0.035 +/- 0.004; P < 0.01). Conclusions-Statins are similar to losartan in attenuating aortic root dilation in a mouse model of Marfan syndrome. They appear to act through reducing the excessive protein manufacture by vascular smooth muscle cells, which occurs in the Marfan aorta. As a drug that is relatively well-tolerated for long-term use, it may be useful clinically. (Circulation. 2011; 124[suppl 1]: S168-S173.)
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据