PUBLICATION
lncExACT1 and DCHS2 Regulate Physiological and Pathological Cardiac Growth
- Authors
- Li, H., Trager, L.E., Liu, X., Hastings, M.H., Xiao, C., Guerra, J., To, S., Li, G., Yeri, A., Rodosthenous, R., Silverman, M.G., Das, S., Ambardekar, A.V., Bristow, M.R., Gonzalez-Rosa, J.M., Rosenzweig, A.
- ID
- ZDB-PUB-220205-2
- Date
- 2022
- Source
- Circulation 145(16): 1218-1233 (Journal)
- Registered Authors
- Gonzalez-Rosa, Juan Manuel
- Keywords
- none
- MeSH Terms
-
- Animals
- Cardiomegaly/metabolism
- Disease Models, Animal
- Heart Failure*
- Humans
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- MicroRNAs*/genetics
- MicroRNAs*/metabolism
- Myocytes, Cardiac/metabolism
- RNA, Long Noncoding*/genetics
- RNA, Long Noncoding*/metabolism
- Zebrafish/genetics
- PubMed
- 35114812 Full text @ Circulation
Citation
Li, H., Trager, L.E., Liu, X., Hastings, M.H., Xiao, C., Guerra, J., To, S., Li, G., Yeri, A., Rodosthenous, R., Silverman, M.G., Das, S., Ambardekar, A.V., Bristow, M.R., Gonzalez-Rosa, J.M., Rosenzweig, A. (2022) lncExACT1 and DCHS2 Regulate Physiological and Pathological Cardiac Growth. Circulation. 145(16):1218-1233.
Abstract
Background The heart grows in response to pathological and physiological stimuli. The former often precedes cardiomyocyte loss and heart failure; the latter paradoxically protects the heart and enhances cardiomyogenesis. The mechanisms underlying these differences remain incompletely understood. While long noncoding RNAs (lncRNAs) are important in cardiac development and disease, less is known about their roles in physiological hypertrophy or cardiomyogenesis.
Methods RNA sequencing was applied to hearts from mice after eight weeks voluntary exercise-induced physiological hypertrophy and cardiomyogenesis or transverse aortic constriction (TAC) for two or eight weeks to induce pathological hypertrophy or heart failure. The top lncRNA candidate was overexpressed in hearts with adeno-associated virus (AAV) vectors and inhibited with antisense locked nucleic acid (LNA)-GapmeRs to examine its function. Downstream effectors were identified through promoter analyses and binding assays. The functional roles of a novel downstream effector, dachsous cadherin-related 2 (DCHS2), were examined through transgenic overexpression in zebrafish and cardiac-specific deletion in Cas9-knockin mice.
Results We identified exercise-regulated cardiac lncRNAs, termed lncExACTs. lncExACT1 was evolutionarily conserved and decreased in exercised hearts but increased in human and experimental heart failure. Cardiac lncExACT1 overexpression caused pathological hypertrophy and heart failure, while lncExACT1 inhibition induced physiological hypertrophy and cardiomyogenesis, protecting against cardiac fibrosis and dysfunction. lncExACT1 functioned by regulating microRNA-222, calcineurin signaling, and Hippo/Yap1 signaling through DCHS2. Cardiomyocyte DCHS2 overexpression in zebrafish induced pathological hypertrophy and impaired cardiac regeneration, promoting scarring after injury. In contrast, murine DCHS2 deletion induced physiological hypertrophy and promoted cardiomyogenesis.
Conclusions These studies identify lncExACT1-DCHS2 as a novel pathway regulating cardiac hypertrophy and cardiomyogenesis. lncExACT1-DCHS2 acts as a master switch toggling the heart between physiological and pathological growth to determine functional outcomes, providing a potentially tractable therapeutic target for harnessing the beneficial effects of exercise.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping