Biomechanical defects and rescue of cardiomyocytes expressing pathologic nuclear lamins
Biomechanical defects and rescue of cardiomyocytes expressing pathologic nuclear lamins
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DOI：
10.1093/cvr/cvy040
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发表时间：
2018-05-01
影响因子：
10.8
通讯作者：
Pricl, Sabrina
中科院分区：
文献类型：
--
作者：
Laurini, Erik;Martinelli, Valentina;Pricl, Sabrina
考虑到LMNA心肌病的临床影响，了解纤层蛋白的功能将满足临床需要，并将导致心力衰竭治疗的进步。采用细胞生物学、原子力显微镜（AFM）和分子建模相结合的多学科方法，在体外新生大鼠心室肌细胞模型上分析了人纤层蛋白A/C基因（LMNA）突变（E161K、D192G、N195K）的生物力学特性。方法与结果三种LMNA突变导致的生物力学缺陷的严重程度与临床表型的严重程度相关。AFM和分子模型鉴定出不同的生物力学和结构变化，分别从E161K到N195K和D192G的严重程度增加。此外，使用p38 MAPK抑制剂修复生物力学缺陷。结论AFM和分子模型能够量化LMNA突变E161K、D192G和N195K中不同的生物力学和结构缺陷，并将缺陷与临床表型严重程度联系起来。细胞生物力学表型的改善已被证实，这可能代表了p38 MAPK抑制疗法的作用机制，目前正用于人类临床试验，以治疗层压板病。
Aims Given the clinical impact of LMNA cardiomyopathies, understanding lamin function will fulfill a clinical need and will lead to advancement in the treatment of heart failure. A multidisciplinary approach combining cell biology, atomic force microscopy (AFM), and molecular modeling was used to analyse the biomechanical properties of human lamin A/C gene (LMNA) mutations (E161K, D192G, N195K) using an in vitro neonatal rat ventricular myocyte model.Methods and results The severity of biomechanical defects due to the three LMNA mutations correlated with the severity of the clinical phenotype. AFM and molecular modeling identified distinctive biomechanical and structural changes, with increasing severity from E161K to N195K and D192G, respectively. Additionally, the biomechanical defects were rescued with a p38 MAPK inhibitor.Conclusions AFM and molecular modeling were able to quantify distinct biomechanical and structural defects in LMNA mutations E161K, D192G, and N195K and correlate the defects with clinical phenotypic severity. Improvements in cellular biomechanical phenotype was demonstrated and may represent a mechanism of action for p38 MAPK inhibition therapy that is now being used in human clinical trials to treat laminopathies.