PDF(Pubmed)
Abstract：
Abdominal aortic aneurysm (AAA) is a critical, multifactorial cardiovascular disorder marked by localized dilatation of the abdominal aorta. A major challenge to countering the pathophysiology of AAAs lies in the naturally irreversible breakdown of elastic fibers in the aorta wall, which is linked to the poor elastogenicity of adult and diseased vascular smooth muscle cells (SMCs) and their impaired ability to assemble mature elastic fibers in a chronic proteolytic tissue milieu. We have previously shown that these are downstream effects of neutrophil elastase-induced activation of the epidermal growth factor receptor (EGFR) activity in aneurysmal SMCs. The novelty of this study lies in investigating the benefits of an EGFR inhibitor drug, afatinib (used to treat nonsmall cell lung cancer), for proelastogenic and antiproteolytic stimulation of aneurysmal SMCs. In in vitro cell cultures, we have shown that safe doses of 0.5 and 1 nM afatinib inhibit EGFR and p-extracellular signal-regulated kinases 1/2 protein expression by 50-70% and downstream elastolytic matrix metalloprotease 2 (MMP2) versus untreated control cultures. In addition, elastin production on a per cell basis was significantly upregulated by afatinib doses within the 0.1-1 nM dose range, which was further validated through transmission electron microscopy showing significantly increased presence of tropoelastin coacervates and maturing elastic fibers upon afatinib treatment at the above doses. Therefore, our studies for the first time demonstrate the therapeutic benefits of afatinib toward use for elastic matrix repair in small AAAs.
摘要：
腹主动脉瘤（AAA）是一个关键，以腹主动脉局部扩张为特征的多因素心血管疾病。对抗AAAs病理生理学的主要挑战在于主动脉壁中弹性纤维的自然不可逆分解，这与成人和患病的血管平滑肌细胞（SMC）的弹性能力差以及它们在慢性蛋白水解组织环境中组装成熟弹性纤维的能力受损有关。我们先前已经表明，这些是中性粒细胞弹性蛋白酶诱导的动脉瘤SMC中表皮生长因子受体（EGFR）活性激活的下游作用。这项研究的新颖性在于研究EGFR抑制剂药物的益处，阿法替尼（用于治疗非小细胞肺癌），用于动脉瘤SMC的前弹性和抗蛋白水解刺激。在体外细胞培养中，我们已经证明,与未处理的对照培养物相比,0.5和1nM的安全剂量阿法替尼抑制50-70%的EGFR和p-细胞外信号调节激酶1/2蛋白表达和下游弹性蛋白酶基质金属蛋白酶2(MMP2).此外,阿法替尼剂量在0.1-1nM剂量范围内，每个细胞的弹性蛋白产生显着上调，这通过透射电镜进一步验证,显示在上述剂量的阿法替尼治疗后,原弹性蛋白凝聚体和成熟弹性纤维的存在显著增加.因此,我们的研究首次证明了阿法替尼在小型AAAs中用于弹性基质修复的治疗益处.
