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LncRNA CCRR maintains Ca 2+ homeostasis against myocardial infarction through the FTO-SERCA2a pathway.
- Source :
-
Science China. Life sciences [Sci China Life Sci] 2024 Aug; Vol. 67 (8), pp. 1601-1619. Date of Electronic Publication: 2024 May 16. - Publication Year :
- 2024
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Abstract
- Cardiac conduction regulatory RNA (CCRR) has been documented as an antiarrhythmic lncRNA in our earlier investigation. This study aimed to evaluate the effects of CCRR on SERCA2a and the associated Ca <superscript>2+</superscript> homeostasis in myocardial infarction (MI). Overexpression of CCRR via AAV9-mediated delivery not only partially reversed ischemia-induced contractile dysfunction but also alleviated abnormal Ca <superscript>2+</superscript> homeostasis and reduced the heightened methylation level of SERCA2a following MI. These effects were also observed in CCRR over-expressing transgenic mice. A conserved sequence domain of CCRR mimicked the protective function observed with the full length. Furthermore, silencing CCRR in healthy mice led to intracellular Ca <superscript>2+</superscript> overloading of cardiomyocytes. CCRR increased SERCA2a protein stability by upregulating FTO expression. The direct interaction between CCRR and FTO protein was characterized by RNA-binding protein immunoprecipitation (RIP) analysis and RNA pulldown experiments. Activation of NFATc3 was identified as an upstream mechanism responsible for CCRR downregulation in MI. This study demonstrates that CCRR is a protective lncRNA that acts by maintaining the function of FTO, thereby reducing the m <superscript>6</superscript> A RNA methylation level of SERCA2a, ultimately preserving calcium homeostasis for myocardial contractile function in MI. Therefore, CCRR may be considered a promising therapeutic strategy with a beneficial role in cardiac pathology.<br /> (© 2024. Science China Press.)
- Subjects :
- Animals
Mice
Male
Mice, Transgenic
Mice, Inbred C57BL
Signal Transduction
Methylation
Humans
Myocardial Infarction metabolism
Myocardial Infarction genetics
Alpha-Ketoglutarate-Dependent Dioxygenase FTO metabolism
Alpha-Ketoglutarate-Dependent Dioxygenase FTO genetics
RNA, Long Noncoding genetics
RNA, Long Noncoding metabolism
Calcium metabolism
Sarcoplasmic Reticulum Calcium-Transporting ATPases metabolism
Sarcoplasmic Reticulum Calcium-Transporting ATPases genetics
Homeostasis
Myocytes, Cardiac metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1869-1889
- Volume :
- 67
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Science China. Life sciences
- Publication Type :
- Academic Journal
- Accession number :
- 38761356
- Full Text :
- https://doi.org/10.1007/s11427-023-2527-5