Muchir Antoine, Shan Jian, Bonne Gisèle, Lehnart Stephan E, Worman Howard J
Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
Hum Mol Genet. 2009 Jan 15;18(2):241-7. doi: 10.1093/hmg/ddn343. Epub 2008 Oct 16.
Autosomal Emery-Dreifuss muscular dystrophy and related disorders with dilated cardiomyopathy and variable skeletal muscle involvement are caused by mutations in LMNA, which encodes A-type nuclear lamins. How alterations in A-type lamins, intermediate filament proteins of the nuclear envelope expressed in most differentiated somatic cells, cause cardiomyopathy is only poorly understood. We demonstrated previously abnormal activation of the extracellular signal-regulated kinase (ERK) branch of the mitogen-activated protein kinase (MAPK) signaling cascade in hearts of Lmna H222P 'knock in' mice, a model of autosomal Emery-Dreifuss muscular dystrophy. We therefore treated Lmna(H222P/H222P) mice that develop cardiomyopathy with PD98059, an inhibitor of ERK activation. Systemic treatment of Lmna(H222P/H222P) mice with PD98059 inhibited ERK phosphorylation and blocked the activation of downstream genes in heart. It also blocked increased expression of RNAs encoding natriuretic peptide precursors and proteins involved in sarcomere organization that occurred in placebo-treated mice. Histological analysis and echocardiography demonstrated that treatment with PD98059 delayed the development of left ventricular dilatation. PD98059-treated Lmna(H222P/H222P) mice had normal cardiac ejection fractions assessed by echocardiography when placebo-treated mice had a 30% decrease. These results emphasize the role of ERK activation in the development of cardiomyopathy caused by LMNA mutations. They further provide proof of principle for ERK inhibition as a therapeutic option to prevent or delay heart failure in humans with Emery-Dreifuss muscular dystrophy and related disorders caused by mutations in LMNA.
常染色体显性遗传的埃默里 - 德赖富斯肌营养不良症及相关疾病伴有扩张型心肌病和可变的骨骼肌受累，是由编码A型核纤层蛋白的LMNA基因突变引起的。A型核纤层蛋白是大多数分化体细胞中表达的核膜中间丝蛋白，其改变如何导致心肌病目前了解甚少。我们之前在常染色体显性遗传的埃默里 - 德赖富斯肌营养不良症模型Lmna H222P“敲入”小鼠的心脏中，证明了丝裂原活化蛋白激酶（MAPK）信号级联的细胞外信号调节激酶（ERK）分支异常激活。因此，我们用ERK激活抑制剂PD98059治疗患有心肌病的Lmna(H222P/H222P)小鼠。用PD98059对Lmna(H222P/H222P)小鼠进行全身治疗可抑制ERK磷酸化，并阻断心脏中下游基因的激活。它还阻断了在接受安慰剂治疗的小鼠中出现的编码利钠肽前体的RNA和参与肌节组织的蛋白质表达增加。组织学分析和超声心动图显示，用PD98059治疗可延缓左心室扩张的发展。当接受安慰剂治疗的小鼠心脏射血分数降低30%时，用PD98059治疗的Lmna(H222P/H222P)小鼠经超声心动图评估的心脏射血分数正常。这些结果强调了ERK激活在由LMNA突变引起的心肌病发展中的作用。它们进一步为ERK抑制作为一种治疗选择提供了原理证明，以预防或延缓患有埃默里 - 德赖富斯肌营养不良症及由LMNA突变引起的相关疾病的人类心力衰竭。
