Department of Medicine, College of Physicians and Surgeons, Columbia University, 630 West 168th Street, 10th Floor, Room 508, New York, NY 10032, USA.
Cardiovasc Res. 2012 Feb 1;93(2):311-9. doi: 10.1093/cvr/cvr301. Epub 2011 Nov 8.
Mutations in A-type nuclear lamins gene, LMNA, lead to a dilated cardiomyopathy. We have reported abnormal activation of the extracellular signal-regulated kinase1/2 (ERK1/2) signalling in hearts from Lmna(H222P/H222P) mice, which develop dilated cardiomyopathy. We therefore determined whether an inhibitor of ERK1/2 signalling that has been investigated in clinical trials for cancer has the potential to be translated to humans with LMNA cardiomyopathy.
To evaluate the relevance of this finding in mice to patients, we analysed the ERK1/2 signalling in heart tissue from human subjects with LMNA cardiomyopathy and showed that it was abnormally activated. To determine whether pharmacological inhibitors of the ERK1/2 signalling pathway could potentially be used to treat LMNA cardiomyopathy, we administered selumetinib to male Lmna(H222P/H222P) mice starting at 16 weeks of age, after they show signs of cardiac deterioration, up to 20 weeks of age. Selumetinib is an inhibitor of ERK1/2 signalling and has been given safely to human subjects in clinical trials for cancer. Systemic treatment with selumetinib inhibited cardiac ERK1/2 phosphorylation and blocked increased expression of RNAs encoding natriuretic peptide precursors and proteins involved in sarcomere architecture that occurred in placebo-treated mice. Echocardiography and histological analysis demonstrated that treatment increases cardiac fractional shortening, prevents myocardial fibrosis, and prolongs survival. Selumetinib treatment did not induce biochemical abnormalities suggestive of renal or hepatic toxicity.
Our results suggest that selumetinib or other related inhibitors that have been safely administered to humans in clinical trials could potentially be used to treat LMNA cardiomyopathy.
A 型核纤层蛋白基因（LMNA）的突变可导致扩张型心肌病。我们曾报道过 Lmna（H222P/H222P）小鼠心脏中细胞外信号调节激酶 1/2（ERK1/2）信号的异常激活，这些小鼠会发展为扩张型心肌病。因此，我们确定了一种已在癌症临床试验中进行研究的 ERK1/2 信号抑制剂是否有可能用于治疗具有 LMNA 心肌病的人类。
为了评估这一发现对小鼠的相关性，我们分析了具有 LMNA 心肌病的人类心脏组织中的 ERK1/2 信号，发现其异常激活。为了确定 ERK1/2 信号通路的药理学抑制剂是否有可能用于治疗 LMNA 心肌病，我们从 16 周龄（此时小鼠开始出现心脏恶化迹象）开始用 selumetinib 治疗雄性 Lmna（H222P/H222P）小鼠，持续至 20 周龄。Selumetinib 是 ERK1/2 信号的抑制剂，已在癌症临床试验中安全地用于人类。全身性使用 selumetinib 抑制了心脏 ERK1/2 磷酸化，并阻断了在安慰剂治疗的小鼠中发生的编码利钠肽前体和参与肌节结构的蛋白质的 RNA 的表达增加。超声心动图和组织学分析表明，治疗可增加心脏的缩短分数，防止心肌纤维化，并延长存活时间。Selumetinib 治疗未引起提示肾或肝毒性的生化异常。
我们的结果表明，selumetinib 或其他已在癌症临床试验中安全用于人类的相关抑制剂，可能可用于治疗 LMNA 心肌病。
