lncExACT1 and DCHS2 Regulate Physiological and Pathological Cardiac Growth
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. Although 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 8 weeks of voluntary exercise-induced physiological hypertrophy and cardiomyogenesis or transverse aortic constriction for 2 or 8 weeks to induce pathological hypertrophy or heart failure. The top lncRNA candidate was overexpressed in hearts with adeno-associated virus vectors and inhibited with antisense locked nucleic acid-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, called 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; 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.
| Errataetall: |
CommentIn: Circulation. 2022 Apr 19;145(16):1234-1237. - PMID 35436132 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:145 |
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| Enthalten in: |
Circulation - 145(2022), 16 vom: 19. Apr., Seite 1218-1233 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Li, Haobo [VerfasserIn] |
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| Links: |
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| Themen: |
Cadherin Related Proteins |
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| Anmerkungen: |
Date Completed 20.04.2022 Date Revised 21.04.2023 published: Print-Electronic CommentIn: Circulation. 2022 Apr 19;145(16):1234-1237. - PMID 35436132 Citation Status MEDLINE |
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| doi: |
10.1161/CIRCULATIONAHA.121.056850 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM336474806 |
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| 245 | 1 | 0 | |a lncExACT1 and DCHS2 Regulate Physiological and Pathological Cardiac Growth |
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| 500 | |a Date Completed 20.04.2022 | ||
| 500 | |a Date Revised 21.04.2023 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a CommentIn: Circulation. 2022 Apr 19;145(16):1234-1237. - PMID 35436132 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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. Although long noncoding RNAs (lncRNAs) are important in cardiac development and disease, less is known about their roles in physiological hypertrophy or cardiomyogenesis | ||
| 520 | |a METHODS: RNA sequencing was applied to hearts from mice after 8 weeks of voluntary exercise-induced physiological hypertrophy and cardiomyogenesis or transverse aortic constriction for 2 or 8 weeks to induce pathological hypertrophy or heart failure. The top lncRNA candidate was overexpressed in hearts with adeno-associated virus vectors and inhibited with antisense locked nucleic acid-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 | ||
| 520 | |a RESULTS: We identified exercise-regulated cardiac lncRNAs, called 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; 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 | ||
| 520 | |a 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 | ||
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| 650 | 4 | |a RNA, long noncoding | |
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| 650 | 4 | |a exercise | |
| 650 | 4 | |a heart failure | |
| 650 | 4 | |a hypertrophy | |
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| 650 | 7 | |a MIRN222 microRNA, human |2 NLM | |
| 650 | 7 | |a MicroRNAs |2 NLM | |
| 650 | 7 | |a RNA, Long Noncoding |2 NLM | |
| 700 | 1 | |a Trager, Lena E |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Xiaojun |e verfasserin |4 aut | |
| 700 | 1 | |a Hastings, Margaret H |e verfasserin |4 aut | |
| 700 | 1 | |a Xiao, Chunyang |e verfasserin |4 aut | |
| 700 | 1 | |a Guerra, Justin |e verfasserin |4 aut | |
| 700 | 1 | |a To, Samantha |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Guoping |e verfasserin |4 aut | |
| 700 | 1 | |a Yeri, Ashish |e verfasserin |4 aut | |
| 700 | 1 | |a Rodosthenous, Rodosthenis |e verfasserin |4 aut | |
| 700 | 1 | |a Silverman, Michael G |e verfasserin |4 aut | |
| 700 | 1 | |a Das, Saumya |e verfasserin |4 aut | |
| 700 | 1 | |a Ambardekar, Amrut V |e verfasserin |4 aut | |
| 700 | 1 | |a Bristow, Michael R |e verfasserin |4 aut | |
| 700 | 1 | |a González-Rosa, Juan Manuel |e verfasserin |4 aut | |
| 700 | 1 | |a Rosenzweig, Anthony |e verfasserin |4 aut | |
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