Zhao Hanjun, Ito Akihiko, Sakai Naohiko, Matsuzawa Yuji, Yamashita Shizuya, Nojima Hiroshi
Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Japan.
Circ J. 2006 May;70(5):615-24. doi: 10.1253/circj.70.615.
RECS1 is a mechanical stress responsive gene and RECS1 knockout (KO) mice (older than 14 months) are prone to cystic medial degeneration (CMD). The present study was designed to assess whether RECS1 KO mice have altered gelatinase (matrix metalloproteinase (MMP)-2 and MMP-9) levels and whether they are prone to aortic dilation.
Aortic and plasma gelatinase levels in RECS1 KO and wild-type (WT) mice were assessed by gelatin zymography and Western blot analysis. Pro-MMP-9 (in the aorta), neutrophil gelatinase-associated lipocalin/MMP-9 complex (NGAL-MMP-9, in plasma), and active-MMP-9 protein levels were more abundant in KO mice throughout adulthood compared with WT mice. Aortic MMP-2, aortic MMP-9, and plasma MMP-9 activation increased with age, even though the aortic pro-MMP-9, plasma NGAL-MMP-9, aortic and plasma pro-MMP-2 production decreased: this was true both for the WT and KO animals. Aortic pro-MMP-2, aortic active-MMP-2, and plasma pro-MMP-2 protein levels were higher in the aged KO mice, but they were lower in the young KO mice than those in WT mice. Thoracic aortic dilation was observed only in the aged KO mice. In situ zymographic experiments confirmed that the increased aortic gelatinase activities were associated with CMD and aortic dilation observed in the aged KO mice.
RECS1 negatively regulates aortic MMP-9 production and knocking out RECS1 induces susceptibility to aortic dilation as well as CMD in the aged mice. The present study suggests that RECS1 plays protective roles in vascular remodeling. We speculate that inhibiting unfavorable deposition and extracellular matrix degradation are both important for prevention and treatment of aneurysms.
RECS1是一种机械应力反应基因，RECS1基因敲除（KO）小鼠（14个月以上）易发生囊性中膜变性（CMD）。本研究旨在评估RECS1基因敲除小鼠的明胶酶（基质金属蛋白酶（MMP）-2和MMP-9）水平是否发生改变，以及它们是否易发生主动脉扩张。
通过明胶酶谱法和蛋白质印迹分析评估RECS1基因敲除小鼠和野生型（WT）小鼠的主动脉和血浆明胶酶水平。与WT小鼠相比，在整个成年期，KO小鼠的前MMP-9（在主动脉中）、中性粒细胞明胶酶相关脂质运载蛋白/MMP-9复合物（NGAL-MMP-9，在血浆中）和活性MMP-9蛋白水平更为丰富。主动脉MMP-2、主动脉MMP-9和血浆MMP-9的激活随年龄增长而增加，尽管主动脉前MMP-9、血浆NGAL-MMP-9、主动脉和血浆前MMP-2的产生减少：WT和KO动物均如此。老年KO小鼠的主动脉前MMP-2、主动脉活性MMP-2和血浆前MMP-2蛋白水平较高，但年轻KO小鼠的这些水平低于WT小鼠。仅在老年KO小鼠中观察到胸主动脉扩张。原位酶谱实验证实，老年KO小鼠中主动脉明胶酶活性增加与CMD和主动脉扩张有关。
RECS1负向调节主动脉MMP-9的产生，敲除RECS1会导致老年小鼠易发生主动脉扩张和CMD。本研究表明RECS1在血管重塑中起保护作用。我们推测抑制不良沉积物和细胞外基质降解对动脉瘤的预防和治疗都很重要。
