Transcription profiling of aorta from mice underexpressing Fibulin-4 to investigate its role in elastic fibre assembly and cardio-vasuclar disease

Extracellular elastic fibres apply structure and mechanical elasticity to organs such as large arteries, lungs and skin 1. Elastic fibres are assembled through polymerization of tropoelastin monomers and loss of elastin is associated with aneurysmal degeneration of the aorta 2. The Fibulins are a six-member protein family hypothesized to function as intermolecular bridges that stabilize the organization of extracellular matrix structures such as elastic fibres and basement membranes 3. Fibulin-4 is found in the medial layers of arteries and moderately expressed in heart valves 4. To examine a potential role of Fibulin-4 in elastic fibre assembly and cardio-vascular disease we generated a mouse model underexpressing Fibulin-4. To get insight into the underlying molecular pathways involved in aneurysm formation, we determined the aorta transcriptome of Fibulin-4R/R animals and identified biological processes that were significantly overrepresented including apoptosis and cell death as well as several novel gene targets implicated in the response to aortic failure. We conclude that decreased Fibulin-4 expression causes aberrant composition of the elastin layers in the aorta and valvular leaflets, resulting in aortic aneurysms and heart abnormalities.细胞外弹性纤维（extracellular elastic fibres）可为大动脉、肺及皮肤等器官提供结构支撑与机械弹性¹。弹性纤维（elastic fibres）通过原弹性蛋白（tropoelastin）单体的聚合反应组装而成，弹性蛋白（elastin）的缺失与主动脉瘤样变性密切相关²。纤丝蛋白家族（Fibulins）是一类包含6个成员的蛋白质家族，被推测可作为分子间桥梁，稳定弹性纤维、基底膜等细胞外基质结构的组织排布³。纤丝蛋白-4（Fibulin-4）表达于动脉中膜层，在心脏瓣膜中呈中等表达水平⁴。为探究纤丝蛋白-4在弹性纤维组装及心血管疾病中的潜在功能，我们构建了低表达纤丝蛋白-4的小鼠模型。为深入解析动脉瘤形成的潜在分子通路，我们对Fibulin-4R/R小鼠的主动脉转录组进行了检测分析，鉴定出多个显著富集的生物学过程，涵盖细胞凋亡与细胞死亡，同时发现了多个与主动脉衰竭应答相关的全新基因靶点。本研究证实，纤丝蛋白-4表达下调会导致主动脉及瓣膜小叶的弹性蛋白层组成异常，最终引发主动脉瘤与心脏异常。