Suppression of Activated FOXO Transcription Factors in the Heart Prolongs Survival in a Mouse Model of Laminopathies.

RATIONALE

Mutations in the 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 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 mouse hearts (<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 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 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 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.