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Systematic in vivo candidate evaluation uncovers therapeutic targets for LMNA dilated cardiomyopathy and risk of Lamin A toxicity.
Tan, Chia Yee; Chan, Pui Shi; Tan, Hansen; Tan, Sung Wei; Lee, Chang Jie Mick; Wang, Jiong-Wei; Ye, Shu; Werner, Hendrikje; Loh, Ying Jie; Lee, Yin Loon; Ackers-Johnson, Matthew; Foo, Roger S Y; Jiang, Jianming.
Affiliation
  • Tan CY; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
  • Chan PS; Centre for Translational Medicine, Cardiovascular Research Institute (CVRI), National University Health System, 14 Medical Drive, Singapore, 117599, Singapore.
  • Tan H; Cardiovascular Disease Translational Research Programme, NUS Yong Loo Lin School of Medicine, 14 Medical Drive, Level 8, Singapore, 117599, Singapore.
  • Tan SW; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
  • Lee CJM; Centre for Translational Medicine, Cardiovascular Research Institute (CVRI), National University Health System, 14 Medical Drive, Singapore, 117599, Singapore.
  • Wang JW; Cardiovascular Disease Translational Research Programme, NUS Yong Loo Lin School of Medicine, 14 Medical Drive, Level 8, Singapore, 117599, Singapore.
  • Ye S; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
  • Werner H; Centre for Translational Medicine, Cardiovascular Research Institute (CVRI), National University Health System, 14 Medical Drive, Singapore, 117599, Singapore.
  • Loh YJ; Cardiovascular Disease Translational Research Programme, NUS Yong Loo Lin School of Medicine, 14 Medical Drive, Level 8, Singapore, 117599, Singapore.
  • Lee YL; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Singapore.
  • Ackers-Johnson M; Centre for Translational Medicine, Cardiovascular Research Institute (CVRI), National University Health System, 14 Medical Drive, Singapore, 117599, Singapore.
  • Foo RSY; Cardiovascular Disease Translational Research Programme, NUS Yong Loo Lin School of Medicine, 14 Medical Drive, Level 8, Singapore, 117599, Singapore.
  • Jiang J; Centre for Translational Medicine, Cardiovascular Research Institute (CVRI), National University Health System, 14 Medical Drive, Singapore, 117599, Singapore.
J Transl Med ; 21(1): 690, 2023 10 16.
Article in En | MEDLINE | ID: mdl-37840136
ABSTRACT

BACKGROUND:

Dilated cardiomyopathy (DCM) is a severe, non-ischemic heart disease which ultimately results in heart failure (HF). Decades of research on DCM have revealed diverse aetiologies. Among them, familial DCM is the major form of DCM, with pathogenic variants in LMNA being the second most common form of autosomal dominant DCM. LMNA DCM is a multifactorial and complex disease with no specific treatment thus far. Many studies have demonstrated that perturbing candidates related to various dysregulated pathways ameliorate LMNA DCM. However, it is unknown whether these candidates could serve as potential therapeutic targets especially in long term efficacy.

METHODS:

We evaluated 14 potential candidates including Lmna gene products (Lamin A and Lamin C), key signaling pathways (Tgfß/Smad, mTor and Fgf/Mapk), calcium handling, proliferation regulators and modifiers of LINC complex function in a cardiac specific Lmna DCM model. Positive candidates for improved cardiac function were further assessed by survival analysis. Suppressive roles and mechanisms of these candidates in ameliorating Lmna DCM were dissected by comparing marker gene expression, Tgfß signaling pathway activation, fibrosis, inflammation, proliferation and DNA damage. Furthermore, transcriptome profiling compared the differences between Lamin A and Lamin C treatment.

RESULTS:

Cardiac function was restored by several positive candidates (Smad3, Yy1, Bmp7, Ctgf, aYAP1, Sun1, Lamin A, and Lamin C), which significantly correlated with suppression of HF/fibrosis marker expression and cardiac fibrosis in Lmna DCM. Lamin C or Sun1 shRNA administration achieved consistent, prolonged survival which highly correlated with reduced heart inflammation and DNA damage. Importantly, Lamin A treatment improved but could not reproduce long term survival, and Lamin A administration to healthy hearts itself induced DCM. Mechanistically, we identified this lapse as caused by a dose-dependent toxicity of Lamin A, which was independent from its maturation.

CONCLUSIONS:

In vivo candidate evaluation revealed that supplementation of Lamin C or knockdown of Sun1 significantly suppressed Lmna DCM and achieve prolonged survival. Conversely, Lamin A supplementation did not rescue long term survival and may impart detrimental cardiotoxicity risk. This study highlights a potential of advancing Lamin C and Sun1 as therapeutic targets for the treatment of LMNA DCM.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cardiomyopathy, Dilated / Cardiomyopathies Limits: Humans Language: En Journal: J Transl Med Year: 2023 Document type: Article Affiliation country: Singapore

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Cardiomyopathy, Dilated / Cardiomyopathies Limits: Humans Language: En Journal: J Transl Med Year: 2023 Document type: Article Affiliation country: Singapore