biostudies-literatureAuguste GNHLBI NIH HHSNIH HHS678-692https://www.ebi.ac.uk/biostudies/studies/S-EPMC5834384biostudies-literatureUnknown122(5)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 Circulation researchSuppression of Activated FOXO Transcription Factors in the Heart Prolongs Survival in a Mouse Model of Laminopathies.PMC5834384R01 HL117641R01 HL132401R01 HL091947S10 OD018135R41 HL129570R01 HL088498R01 HL089598Auguste GGurha PCoarfa CMarian AJWillerson JTLombardi RfalseSuppression of Activated FOXO Transcription Factors in the Heart Prolongs Survival in a Mouse Model of Laminopathies.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 2018-01-01T00:00:00Z2018 Mar2025-04-19T15:19:45.812Z2019-08-04T07:29:49ZS-EPMC58343842931743110.1161/circresaha.117.31205210.1161/CIRCRESAHA.117.312052