Key result
Deletion of the Lmna gene in fibroblasts caused cardiac conduction defects, arrhythmias, and premature death within the first 6 weeks of life, with differential expression of ~410 genes.
Why the study?
Dilated cardiomyopathy is primarily considered a disease of cardiac myocytes, but LMNA is also expressed in fibroblasts; the contribution of fibroblasts to LMNA-deficiency DCM was unknown.
Fibroblast-specific deletion of the Lmna gene in mice partially recapitulates LMNA-associated dilated cardiomyopathy, highlighting the contribution of non-myocyte cells to the disease phenotype.
Fibroblast LMNA effects may drive DCM in mice; leaves open human relevance and therapeutic targeting.
Introduction: Mutations in the LMNA gene, encoding Lamin A/C (LMNA), are established causes of dilated cardiomyopathy (DCM). The phenotype is typically characterized by progressive cardiac conduction defects, arrhythmias, heart failure, and premature death. DCM is primarily considered a disease of cardiac myocytes. However, LMNA is also expressed in other cardiac cell types, including fibroblasts. Aim: The purpose of the study was to determine the contribution of the fibroblasts to DCM caused by LMNA deficiency. Methods and Results: The Lmna gene was deleted by crossing the platelet-derived growth factor receptor α-Cre recombinase (Pdgfra-Cre) and floxed Lmna (LmnaF/F) mice. The LMNA protein was nearly absent in ~80% of the cardiac fibroblasts and ~25% of cardiac myocytes in the Pdgfra-Cre:LmnaF/F mice. The Pdgfra-Cre:LmnaF/F mice showed an early phenotype characterized by cardiac conduction defects, arrhythmias, cardiac dysfunction, myocardial fibrosis, apoptosis, and premature death within the first six weeks of life. The Pdgfra-Cre:LmnaWild type/F(LmnaW/F) mice also showed a similar but slowly evolving phenotype that was expressed within one year of age. RNA sequencing of LMNA-deficient and wild-type cardiac fibroblasts identified differential expression of ~410 genes, which predicted activation of the TP53 and TNFA/NFκB and suppression of the cell cycle pathways. In agreement with these findings, levels of phospho-H2AFX, ATM, phospho-TP53, and CDKN1A, markers of the DNA damage response (DDR) pathway, were increased in the Pdgfra-Cre:LmnaF/F mouse hearts. Moreover, expression of senescence-associated beta-galactosidase was induced and levels of the senescence-associated secretory phenotype (SASP) proteins TGFβ1, CTGF (CCN2), and LGLAS3 were increased as well as the transcript levels of additional genes encoding SASP proteins in the Pdgfra-Cre:LmnaF/F mouse hearts. Finally, expression of pH2AFX, a bonafide marker of the double-stranded DNA breaks, was increased in cardiac fibroblasts isolated from the Pdgfra-Cre:LmnaF/F mouse hearts. Conclusion: Deletion of the Lmna gene in fibroblasts partially recapitulates the phenotype of the LMNA-associated DCM, likely through induction of double-stranded DNA breaks, activation of the DDR pathway, and induction of expression of the SASP proteins. The findings indicate that the phenotype in the LMNA-associated DCM is the aggregate consequence of the LMNA deficiency in multiple cardiac cells, including cardiac fibroblasts.
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Rouhi et al. (2022) studied Dilated cardiomyopathy. Deletion of the Lmna gene in fibroblasts vs. Wild-type mice/fibroblasts was evaluated on Cardiac conduction defects, arrhythmias, cardiac dysfunction, myocardial fibrosis, apoptosis, and premature death. Deletion of the Lmna gene in fibroblasts caused cardiac conduction defects, arrhythmias, and premature death within the first 6 weeks of life, with differential expression of ~410 genes.
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