Olmesartan Restores LMNA Function in Haploinsufficient Cardiomyocytes
(2025) In Circulation 151(20). p.1436-1448- Abstract
BACKGROUND: Gene mutations are responsible for a sizeable proportion of cases of heart failure. However, the number of patients with any specific mutation is small. Repositioning of existing US Food and Drug Administration-approved compounds to target specific mutations is a promising approach to efficient identification of new therapies for these patients. METHODS: The National Institutes of Health Library of Integrated Network-Based Cellular Signatures database was interrogated to identify US Food and Drug Administration-approved compounds that demonstrated the ability to reverse the transcriptional effects of LMNA knockdown. Top hits from this screening were validated in vitro with patient-specific induced pluripotent stem... (More)
BACKGROUND: Gene mutations are responsible for a sizeable proportion of cases of heart failure. However, the number of patients with any specific mutation is small. Repositioning of existing US Food and Drug Administration-approved compounds to target specific mutations is a promising approach to efficient identification of new therapies for these patients. METHODS: The National Institutes of Health Library of Integrated Network-Based Cellular Signatures database was interrogated to identify US Food and Drug Administration-approved compounds that demonstrated the ability to reverse the transcriptional effects of LMNA knockdown. Top hits from this screening were validated in vitro with patient-specific induced pluripotent stem cell-derived cardiomyocytes combined with force measurement, gene expression profiling, electrophysiology, and protein expression analysis. RESULTS: Several angiotensin receptor blockers were identified from our in silico screen. Of these, olmesartan significantly elevated the expression of sarcomeric genes and rate and force of contraction and ameliorated arrhythmogenic potential. In addition, olmesartan exhibited the ability to reduce phosphorylation of extracellular signal-regulated kinase 1 in LMNA-mutant induced pluripotent stem cell-derived cardiomyocytes. CONCLUSIONS: In silico screening followed by in vitro validation with induced pluripotent stem cell-derived models can be an efficient approach to identifying repositionable therapies for monogenic cardiomyopathies.
(Less)
- author
- Kort, Eric J. ; Sayed, Nazish ; Liu, Chun ; Mondéjar-Parreño, Gema ; Forsberg, Jens ; Eugster, Emily ; Wu, Sean M. ; Wu, Joseph C. and Jovinge, Stefan LU
- organization
- publishing date
- 2025-05
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- cardiomyopathies, drug repositioning, gene expression profiling, lamins
- in
- Circulation
- volume
- 151
- issue
- 20
- pages
- 13 pages
- publisher
- Lippincott Williams & Wilkins
- external identifiers
-
- scopus:105002437026
- pmid:40166828
- ISSN
- 0009-7322
- DOI
- 10.1161/CIRCULATIONAHA.121.058621
- language
- English
- LU publication?
- yes
- id
- 95179927-0b45-456a-ad2e-aaa5c9297673
- date added to LUP
- 2025-08-28 12:52:51
- date last changed
- 2025-08-29 03:00:03
@article{95179927-0b45-456a-ad2e-aaa5c9297673,
abstract = {{<p>BACKGROUND: Gene mutations are responsible for a sizeable proportion of cases of heart failure. However, the number of patients with any specific mutation is small. Repositioning of existing US Food and Drug Administration-approved compounds to target specific mutations is a promising approach to efficient identification of new therapies for these patients. METHODS: The National Institutes of Health Library of Integrated Network-Based Cellular Signatures database was interrogated to identify US Food and Drug Administration-approved compounds that demonstrated the ability to reverse the transcriptional effects of LMNA knockdown. Top hits from this screening were validated in vitro with patient-specific induced pluripotent stem cell-derived cardiomyocytes combined with force measurement, gene expression profiling, electrophysiology, and protein expression analysis. RESULTS: Several angiotensin receptor blockers were identified from our in silico screen. Of these, olmesartan significantly elevated the expression of sarcomeric genes and rate and force of contraction and ameliorated arrhythmogenic potential. In addition, olmesartan exhibited the ability to reduce phosphorylation of extracellular signal-regulated kinase 1 in LMNA-mutant induced pluripotent stem cell-derived cardiomyocytes. CONCLUSIONS: In silico screening followed by in vitro validation with induced pluripotent stem cell-derived models can be an efficient approach to identifying repositionable therapies for monogenic cardiomyopathies.</p>}},
author = {{Kort, Eric J. and Sayed, Nazish and Liu, Chun and Mondéjar-Parreño, Gema and Forsberg, Jens and Eugster, Emily and Wu, Sean M. and Wu, Joseph C. and Jovinge, Stefan}},
issn = {{0009-7322}},
keywords = {{cardiomyopathies; drug repositioning; gene expression profiling; lamins}},
language = {{eng}},
number = {{20}},
pages = {{1436--1448}},
publisher = {{Lippincott Williams & Wilkins}},
series = {{Circulation}},
title = {{Olmesartan Restores LMNA Function in Haploinsufficient Cardiomyocytes}},
url = {{http://dx.doi.org/10.1161/CIRCULATIONAHA.121.058621}},
doi = {{10.1161/CIRCULATIONAHA.121.058621}},
volume = {{151}},
year = {{2025}},
}