Center for Cardiovascular Genetics, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, and Department of Medicine, University of Texas Health Sciences Center at Houston, Houston, Texas, USA.
Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA.
J Clin Invest. 2020 Sep 1;130(9):4740-4758. doi: 10.1172/JCI135922.
Mutation in the LMNA gene, encoding lamin A/C, causes a diverse group of diseases called laminopathies. Cardiac involvement is the major cause of death and manifests as dilated cardiomyopathy, heart failure, arrhythmias, and sudden death. There is no specific therapy for LMNA-associated cardiomyopathy. We report that deletion of Lmna in cardiomyocytes in mice leads to severe cardiac dysfunction, conduction defect, ventricular arrhythmias, fibrosis, apoptosis, and premature death within 4 weeks. The phenotype is similar to LMNA-associated cardiomyopathy in humans. RNA sequencing, performed before the onset of cardiac dysfunction, led to identification of 2338 differentially expressed genes (DEGs) in Lmna-deleted cardiomyocytes. DEGs predicted activation of bromodomain-containing protein 4 (BRD4), a regulator of chromatin-associated proteins and transcription factors, which was confirmed by complementary approaches, including chromatin immunoprecipitation sequencing. Daily injection of JQ1, a specific BET bromodomain inhibitor, partially reversed the DEGs, including those encoding secretome; improved cardiac function; abrogated cardiac arrhythmias, fibrosis, and apoptosis; and prolonged the median survival time 2-fold in the myocyte-specific Lmna-deleted mice. The findings highlight the important role of LMNA in cardiomyocytes and identify BET bromodomain inhibition as a potential therapeutic target in LMNA-associated cardiomyopathy, for which there is no specific effective therapy.
编码核纤层蛋白 A/C 的 LMNA 基因突变会导致一组称为核纤层病的多种疾病。心脏受累是主要的死亡原因，表现为扩张型心肌病、心力衰竭、心律失常和猝死。目前尚无针对 LMNA 相关心肌病的特定治疗方法。我们报告说，在小鼠心肌细胞中敲除 Lmna 会导致严重的心脏功能障碍、传导缺陷、室性心律失常、纤维化、细胞凋亡和 4 周内过早死亡。这种表型类似于人类的 LMNA 相关心肌病。在心脏功能障碍出现之前进行的 RNA 测序导致在 Lmna 缺失的心肌细胞中鉴定出 2338 个差异表达基因 (DEG)。DEG 预测了溴结构域蛋白 4 (BRD4)的激活，BRD4 是染色质相关蛋白和转录因子的调节剂，通过包括染色质免疫沉淀测序在内的互补方法得到了证实。每天注射 BRD4 的特异性 BET 溴结构域抑制剂 JQ1，部分逆转了 DEG，包括那些编码分泌组的基因；改善了心脏功能；消除了心脏心律失常、纤维化和细胞凋亡；并将肌细胞特异性 Lmna 缺失小鼠的中位生存时间延长了 2 倍。这些发现强调了 LMNA 在心肌细胞中的重要作用，并确定 BET 溴结构域抑制作为一种潜在的治疗靶点，用于治疗目前尚无特效疗法的 LMNA 相关心肌病。
