Abstract 15820: Early and Pre-clinical Transcriptome Analysis by RNA Sequencing Identifies Mitochondrial Dysfunction and Inflammation as Early Phenotypic Consequences of Lamin A/C Deficiency
Introduction: Mutations in the LMNA gene, encoding Lamin A/C, cause several distinct phenotypes collectively referred to as laminopathies. Cardiac involvement is the primary cause of death and manifests as dilated cardiomyopathy (DCM), conduction defects, arrhythmias, and sudden cardiac death. The pathogenesis of cardiac phenotype in laminopathies remains largely unknown.
Hypothesis: We posit that early pre-clinical RNA-Sequencing could identify the primary events in the heart in laminopathies.
Methods: Lmna-/- and control wild type (WT) mice were characterized for cardiac function (echocardiography) and cardiac histology at 2 and 4 weeks. Transcriptome was analyzed by RNA-Seq at 2 weeks, prior to expression of cardiac dysfunction, apoptosis, and fibrosis.
Results: Hierarchal clustering of 908 differentially expressed transcripts in the heart (q<0.05) showed distinct separation of the Lmna-/- and WT mice. Hypergeometric distribution of the enriched transcription factors (TFs) identified FOXO4 and E2F1 as the most hyperrepresented TFs in the upregulated and downregulated genes in the Lmna-/- hearts, respectively. Pathway analysis identified down-regulation of mitochondrial OXPHOS and upregulation of the inflammatory pathways in the Lmna-/- heart. In accord with the RNA-Seq data, mitochondrial electron transport chain activity of complex I was significantly reduced, as were the transcripts levels of the nuclear genes encoding complex I proteins. Consistent with mitochondrial dysfunction, levels of cytokines CXCL1, CCL2, IL6, CXCL10, IL9, and LIF and their corresponding transcripts were increased in the Lmna-/- hearts. Mitochondrial dysfunction and increased myocardial cytokine levels preceded cardiac dysfunction, myocardial apoptosis, fibrosis and premature death, resulting in ~ 50% mortality at 4 week of age in the Lmna-/- mice.
Conclusions: Whole transcriptome analysis identifies mitochondrial dysfunction and myocardial inflammation, in part regulated by FOXO4 and E2F1 pathways, as early phenotypes preceding cardiac dysfunction and premature death. The findings implicate inflammation as a therapeutic target in cardiac involvement in laminopathies.
Author Disclosures: G. Auguste: None. P. Gurha: None. C. Coarfa: None. R. Lombardi: None. B.H. Graham: None. A.J. Marian: None.
- © 2016 by American Heart Association, Inc.