Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of Lysyl Oxidase. Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of Lysyl Oxidase

Purpose: Arterial stiffening is a hallmark of premature aging in Hutchinson-Gilford Progeria Syndrome (HGPS), but the molecular regulators remain unknown. Here, we show that the LMNAG609G mouse model of HGPS recapitulates the premature arterial stiffening seen in human HGPS. To gain a better understanding of potential stiffness-regulators in LMNAG609G mice, we performed RNA-sequencing analysis on cleaned descending aortas from 2- and 24-month WT and 2-month LMNAG609G mice on a C57BL6 background. Methods: Descending aortas containing the intimal, medial and adventitial layers were isolated from 2- and 24-month male WT and 2-month HGPS mice, and RNA was extracted using the RNeasy Plus Micro kit (Qiagen 74034). The high-throughput library was prepared using the TruSeq stranded total RNA (ribo-Zero) kit (Illumina 20037135). Paired-end sequencing was performed on a HiSeq4000 Sequencing System (Illumina) and generated 14-30 million reads/sample. Overall design: Aortic mRNA profiles of young and old wild type (WT) and young LMNAG609G mice.

研究背景与目的：动脉僵硬是哈金森-吉尔福德早衰综合征（Hutchinson-Gilford Progeria Syndrome, HGPS）过早衰老的标志性病理特征，但其分子调控机制仍未明晰。本研究证实，携带LMNAG609G突变的HGPS小鼠模型可重现人类HGPS患者所见的过早动脉僵硬表型。为深入解析LMNAG609G小鼠中潜在的动脉僵硬调控因子，我们对C57BL/6遗传背景下的2月龄、24月龄野生型（Wild Type, WT）小鼠，以及2月龄LMNAG609G小鼠的纯化降主动脉开展了RNA测序分析。

实验方法：分别从2月龄及24月龄雄性野生型小鼠、2月龄HGPS模型小鼠体内分离包含内膜、中膜及外膜三层结构的降主动脉，采用RNeasy Plus Micro试剂盒（Qiagen 74034）提取总RNA。使用TruSeq链特异性总RNA（Ribo-Zero）试剂盒（Illumina 20037135）构建高通量测序文库。依托HiSeq4000测序系统（Illumina）完成双端测序，每个样本可获得1400万至3000万条测序读段。

整体实验设计：年轻与老年野生型小鼠及年轻LMNAG609G模型小鼠的主动脉mRNA表达谱。