Rationale: Mutations in the LMNA gene, encoding nuclear inner membrane protein lamin A/C, cause distinct phenotypes, collectively referred to as laminopathies. Heart failure, conduction defects, and arrhythmias are the common causes of death in laminopathies.

Objective: The objective of this study was to identify and therapeutically target the responsible mechanism(s) for cardiac phenotype in laminopathies.

Methods and Results: Whole-heart RNA sequencing was performed before the onset of cardiac dysfunction in the Lmna^−/− and matched control mice. Differentially expressed transcripts and their upstream regulators were identified, validated, and targeted by adeno-associated virus serotype 9-short hairpin RNA constructs. A total of 576 transcripts were upregulated and 233 were downregulated in the Lmna^−/− mouse hearts (q<0.05). Forkhead box O (FOXO) transcription factors (TFs) were the most activated while E2 factors were the most suppressed transcriptional regulators. Transcript levels of FOXO targets were also upregulated in the isolated Lmna^−/− cardiac myocytes and in the myocardium of human heart failure patients. Nuclear localization of FOXO1 and 3 was increased, whereas phosphorylated (inactive) FOXO1 and 3 levels were reduced in the Lmna^−/− hearts. Gene set enrichment analysis and gene ontology showed activation of apoptosis and inflammation and suppression of cell cycle, adipogenesis, and oxidative phosphorylation in the Lmna^−/− hearts. Adeno-associated virus serotype 9-short hairpin RNA–mediated suppression of FOXO TFs rescued selected molecular signatures, improved apoptosis, and prolonged survival by ≈2-fold.

Conclusions: FOXO TFs are activated and contribute to the pathogenesis of cardiac phenotype in laminopathies. Suppression of the FOXO TFs in cardiac myocytes partially rescues the phenotype and prolongs survival. The findings identify FOXO TFs as potential therapeutic targets for cardiac phenotype in laminopathies.

原理：编码核内膜蛋白层粘连蛋白A / C的LMNA基因突变会导致明显的表型，统称为laminopathies。心力衰竭，传导缺陷和心律不齐是造成椎间盘突出症的常见死亡原因。

目的：本研究的目的是确定和治疗靶向于椎管病的心脏表型的负责机制。

方法和结果：在Lmna ^-/-和配对对照小鼠的心脏功能障碍发作之前进行全心RNA测序。通过腺相关病毒血清型9-短发夹RNA构建体鉴定，验证和靶向差异表达的转录本及其上游调节子。在Lmna ^-/-小鼠心脏中，总共有576个转录本被上调，而233个被下调（ q <0.05）。叉头盒O（FOXO）转录因子（TFs）激活最强，而E2因子是抑制性最强的转录调节因子。在分离的Lmna ^-/-中，FOXO目标的转录水平也被上调心肌细胞和人类心力衰竭患者的心肌中。在Lmna ^-/-心脏中，FOXO1和3的核定位增加，而磷酸化（非活性）FOXO1和3的水平降低。基因集富集分析和基因本体论显示了Lmna ^-/-心脏中细胞凋亡和炎症的激活以及细胞周期，脂肪形成和氧化磷酸化的抑制。腺相关病毒血清型9-短发夹RNA介导的FOXO TFs的抑制作用挽救了选定的分子标记，改善了细胞凋亡，并使生存期延长了约2倍。

结论： FOXO TFs被激活并促进了lamanopathies心脏表型的发病机理。心肌细胞中FOXO TF的抑制可部分挽救表型并延长生存期。这些发现将FOXO TFs确定为潜在的治疗心脏疾病表型的靶标。