Stan W van Wijk, Puck Vree, Fabries G Huiskes, Reinier L van der Palen, Aiste Liutkute, Niels Voigt, Lori L Wallrath, Bianca J J M Brundel
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引用次数: 0
摘要
房颤(AF)是最常见的进行性心律失常,与中风和心力衰竭等严重并发症有关。虽然共同的危险因素是房颤发病的基础,但在15%的受影响人群中,房颤可能有遗传原因。在这里,我们研究LMNA变异是如何引起心律失常的。由此产生的黑腹果蝇菌株具有与人类LMNA同源的果蝇类似的变体,称为Lamin C (LamC)。分别记录速搏前(BTP)和速搏后(ATP)预蛹的心壁运动。与BTP相比,表达野生型LamC (WT)、ΔN和p.R205W的果蝇心率(HR)ATP显著降低,但心律失常指数(AI)ATP不受影响。与BTP相比,LamC p.N210K和p.R264Q显著降低HRATP,增加AIATP。LamC p.N210K和LamC p.R264Q在微管稳定剂紫杉醇的药物干预后显示出相互矛盾的作用。紫杉醇可减弱LamC p.N210K的致心律失常作用,但可加重p.R264Q的致心律失常作用。研究结果表明,不同的纤层蛋白变体触发不同的分子途径,驱动果蝇的心律失常效应。
Lamin variants cause cardiac arrhythmogenicity in Drosophila.
Atrial fibrillation (AF), the most common progressive cardiac arrhythmia, is associated with serious complications such as stroke and heart failure. Although common risk factors underlie AF onset, in 15% of the affected population, AF may have a genetic cause. Here, we investigated how LMNA variants cause cardiac arrhythmicity. Drosophila melanogaster strains were generated possessing the analogous variants in the Drosophila orthologue of human lamin A/C (LMNA), Lamin C (LamC). Heart wall movements in prepupae were recorded before (BTP) and after (ATP) tachypacing. ATP, flies expressing wild-type LamC, and the variants ΔN and p.R205W showed a significant reduction in heart rate (HR), but the arrhythmia index (AI) was not affected, compared to BTP. By contrast, those expressing p.N210K and p.R264Q showed a significant reduction in HR and increased AI, compared to BTP. p.N210K- and p.R264Q-expressing prepupae showed contrasting effects after pharmacological intervention with microtubule stabilizer taxol. Taxol attenuated the arrhythmogenicity in p.N210K-expressing prepupae, but aggravated it in p.R264Q-expressing prepupae. These findings suggest that different lamin variants trigger distinct molecular pathways that drive arrhythmogenic effects in Drosophila.
期刊介绍:
Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.