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Updated: Jul 11, 2025
Studying RNA Interactors of Protein Kinase RNA-Activated during the Mammalian Cell Cycle
Published on: March 5, 2019
Abnormal expression of PRKAG2-AS results in dysfunction of cardiomyocytes through regulating PRKAG2 transcription by
Xiao-Wei Song1, Ting Su2, Bo Li2
1Department of Cardiology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, China. xiao_wei_song@163.com.
Insights
The long non-coding RNA PRKAG2-AS regulates PRKAG2 expression in cardiomyocytes. Aberrant PRKAG2-AS expression is linked to heart dysfunction, including ischemic and dilated cardiomyopathy.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Epigenetics
Background:
- The role of PRKAG2 in heart function is known, but its regulation in cardiomyocytes is unclear.
- Long non-coding RNAs (lncRNAs) are emerging as key regulators of gene expression.
Purpose of the Study:
- To investigate the role of the lncRNA PRKAG2-AS in regulating PRKAG2 expression in cardiomyocytes.
- To explore the involvement of PRKAG2-AS in cardiac dysfunction, including ischemic and dilated cardiomyopathy.
Main Methods:
- RNA nucleoplasmic separation and fluorescence in situ hybridization to determine PRKAG2-AS localization.
- PRKAG2-AS knockdown in cardiomyocytes to assess effects on PRKAG2b and PRKAG2d expression.
- Analysis of PRKAG2-AS and target gene expression in patient heart samples (ischemic and dilated cardiomyopathy).
- Protein-RNA interaction analysis to identify PRKAG2-AS binding partners, focusing on PPARG.
- Overexpression and activation studies of PPARG and its effects on PRKAG2 expression.
Main Results:
- PRKAG2-AS is predominantly localized in the nucleus of cardiomyocytes.
- Nuclear knockdown of PRKAG2-AS significantly reduced PRKAG2b and PRKAG2d expression.
- PRKAG2-AS and its target genes were downregulated in ischemic cardiomyopathy but upregulated in dilated cardiomyopathy.
- PRKAG2-AS knockdown in the nucleus induced cardiomyocyte apoptosis.
- PPARG interacts with PRKAG2-AS and mediates PRKAG2b/d expression; rosiglitazone's protective effects against hypoxia-induced apoptosis are PRKAG2-AS dependent.
- Overexpression of PRKAG2-AS increased PRKAG2b/d expression, suggesting its role in heart failure mechanisms.
Conclusions:
- PRKAG2-AS is a nuclear-encoded lncRNA crucial for regulating PRKAG2 expression in cardiomyocytes.
- Aberrant PRKAG2-AS expression, influenced by factors like hypoxia, contributes to cardiac dysfunction and heart failure.
- PRKAG2-AS plays a dual role in cardiac pathology, being downregulated in ischemia but upregulated in dilated cardiomyopathy.
Abstract:
The role of PRKAG2 in the maintenance of heart function is well established, but little is known about how PRKAG2 is regulated in cardiomyocytes. In this study, we investigated the role of the lncRNA PRKAG2-AS, which is present at the PRKAG2 promoter, in the regulation of PRKAG2 expression. PRKAG2-AS expression was predominantly nuclear, as determined by RNA nucleoplasmic separation and fluorescence in situ hybridization. Knockdown of PRKAG2-AS in the nucleus, but not the cytoplasm, significantly decreased the expression of PRKAG2b and PRKAG2d. Interestingly, we found that PRKAG2-AS and its target genes, PRKAG2b and PRKAG2d, were reduced in the hearts of patients with ischemic cardiomyopathy, suggesting a potential role for PRKAG2-AS in myocardial ischemia. Indeed, knockdown of PRKAG2-AS in the nucleus resulted in apoptosis of cardiomyocytes. We further elucidated the mechanism by which PRKAG2-AS regulates PRKAG2 transcription by identifying 58 PRKAG2-AS interacting proteins. Among them, PPARG was selected for further investigation based on its correlation and potential interaction with PRKAG2-AS in regulating transcription. Overexpression of PPARG, or its activation with rosiglitazone, led to a significant increase in the expression of PRKAG2b and PRKAG2d in cardiomyocytes, which could be attenuated by PRKAG2-AS knockdown. This finding suggests that PRKAG2-AS mediates, at least partially, the protective effects of rosiglitazone on hypoxia-induced apoptosis. However, given the risk of rosiglitazone in heart failure, we also examined the involvement of PRKAG2-AS in this condition and found that PRKAG2-AS, as well as PRKAG2b and PRKAG2d, was elevated in hearts with dilated cardiomyopathy (DCM) and that overexpression of PRKAG2-AS led to a significant increase in PRKAG2b and PRKAG2d expression, indicating that up-regulation of PRKAG2-AS may contribute to the mechanism of heart failure by promoting transcription of PRKAG2. Consequently, proper expression of PRKAG2-AS is essential for maintaining cardiomyocyte function, and aberrant PRKAG2-AS expression induced by hypoxia or other stimuli may cause cardiac dysfunction.
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