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首页> 外文期刊>EBioMedicine >A functional variant of SMAD4 enhances thoracic aortic aneurysm and dissection risk through promoting smooth muscle cell apoptosis and proteoglycan degradation
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A functional variant of SMAD4 enhances thoracic aortic aneurysm and dissection risk through promoting smooth muscle cell apoptosis and proteoglycan degradation

机译：SMAD4的功能性变体通过促进平滑肌细胞凋亡和蛋白聚糖降解来增强胸主动脉瘤和解剖风险

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Recent studies indicate important roles for SMAD4 in SMCs proliferation, extracellular matrix maintenance, and blood vessel remodeling. However, the genetic effects of SMAD4 in the pathogenesis of thoracic aortic aneurysm and dissection (TAAD) are still largely unknown. Here we identified a functional variant of SMAD4 which might be involved in the pathological progression of TAAD. Five tagging SNPs of SMAD4 were genotyped in 202 TAAD cases and 400 controls using MALDI-TOF. rs12455792 CT or TT variant genotypes was associated with an significantly elevated TAAD risk (adjusted OR=1.58, 95%CI=1.09-2.30) under a dominant genetic model. It was located in the 5'UTR and predicted to influence transcription activity and RNA folding of SMAD4. In luciferase reporter assay, rs12455792 T allele markedly decreased luciferase activities. Accordingly, SMAD4 expression in tissues was lower in patients with CT or TT genotypes, compared with CC. Movat's pentachrome showed that rs12455792 T allele enhanced SMCs loss and fibers accumulation. With angiotensin II induction, rate of Apoptotic SMCs was significantly higher while SMAD4 silenced. Moreover, rs12455792 T allele also increased Versican degradation via ADAMTS-4. In conclusion, this variant might promote SMCs apoptosis and proteoglycans degradation, and further facilitate the progress of TAAD. Our findings identified rs12455792 as a predictor for progression of vascular media pathological changes related thoracic aortic disorders.
机译：最近的研究表明SMAD4在SMC增殖，细胞外基质维持和血管重塑中起重要作用。然而，SMAD4在胸主动脉瘤和夹层（TAAD）发病机理中的遗传作用仍然未知。在这里我们确定了SMAD4的功能变异，可能与TAAD的病理进程有关。使用MALDI-TOF在202例TAAD病例和400例对照中对SMAD4的5个标记SNP进行了基因分型。在显性遗传模型下，rs12455792 CT或TT变异基因型与TAAD风险显着升高相关（校正后OR = 1.58，95％CI = 1.09-2.30）。它位于5'UTR中，预计会影响SMAD4的转录活性和RNA折叠。在荧光素酶报告基因分析中，rs12455792 T等位基因显着降低了荧光素酶活性。因此，与CC相比，具有CT或TT基因型的患者在组织中的SMAD4表达较低。 Movat的五色体表明rs12455792 T等位基因可增强SMC的丢失和纤维积累。通过血管紧张素II诱导，SMAD4沉默时凋亡SMC的发生率明显更高。此外，rs12455792 T等位基因还通过ADAMTS-4增加了Versican降解。总之，该变体可能促进SMCs的凋亡和蛋白聚糖降解，并进一步促进TAAD的进展。我们的发现将rs12455792确定为与胸主动脉疾病相关的血管介质病理变化进展的预测因子。

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