Deletion of the Lmna gene in fibroblasts causes senescence-associated dilated cardiomyopathy by activating the double-stranded DNA damage response and induction of senescence-associated secretory phenotype

被引:18
作者
Rouhi, Leila [1 ]
Auguste, Gaelle [1 ]
Zhou, Qiong [2 ,3 ]
Lombardi, Raffaella [4 ]
Olcum, Melis [1 ]
Pourebrahim, Kimia [1 ]
Cheedipudi, Sirisha M. [1 ]
Asghar, Saman [1 ]
Hong, Kui [2 ,3 ]
Robertson, Matthew J. [5 ]
Coarfa, Cristian [6 ]
Gurha, Priyatansh [1 ]
Marian, Ali J. [1 ]
机构
[1] Univ Texas, Inst Mol Med, Ctr Cardiovasc Genet, Hlth Sci Ctr, 6770 Bertner Ave,Suite C900A, Houston, TX 77030 USA
[2] Nanchang Univ, Affiliated Hosp 2, Dept Cardiovasc Med, Nanchang 330006, Jiangxi, Peoples R China
[3] Nanchang Univ, Affiliated Hosp 2, Jiangxi Key Lab Mol Med, Nanchang 330006, Jiangxi, Peoples R China
[4] Univ Naples Federico II, Dept Adv Biomed Sci, Div Cardiol, I-80100 Naples, Italy
[5] 10x Genom, San Francisco, CA 94111 USA
[6] Baylor Coll Med, Dept Mol & Cellular Biol, Houston, TX 77030 USA
来源
JOURNAL OF CARDIOVASCULAR AGING | 2022年 / 2卷 / 03期
关键词
Fibroblasts; senescence; fibrosis; apoptosis; lamin A/C; heart failure; cardiomyopathy; LAMIN A/C GENE; HYPERTROPHY; MUTATIONS; CARRIERS; DISEASE;
D O I
10.20517/jca.2022.14
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 alpha-Cre recombinase (Pdgfra-Cre) and floxed Lmna (Lmna(F/F)) mice. The LMNA protein was nearly absent in similar to 80% of the cardiac fibroblasts and similar to 25% of cardiac myocytes in the Pdgfra-Cre:Lmna(F/F) mice. The Pdgfra-Cre:Lmna(F/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:Lmna(Wild type/F)(Lmna(W/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 similar to 410 genes, which predicted activation of the TP53 and TNFA/NF kappa B 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:Lmna(F/F) mouse hearts. Moreover, expression of senescence-associated beta-galactosidase was induced and levels of the senescence-associated secretory phenotype (SASP) proteins TGF beta 1, CTGF (CCN2), and LGLAS3 were increased as well as the transcript levels of additional genes encoding SASP proteins in the Pdgfra-Cre:Lmna(F/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:Lmna(F/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. One sentence summary: Cardiac fibroblasts contribute to the pathogenesis of DCM - associated with LMNA deficiency through activation of the senescence-associated secretory phenotype.
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页数:24
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