Analysis of Cell Type-Specific Effects of MicroRNA-92a Provides Novel Insights Into Target Regulation and Mechanism of Action. Rogg, E., Abplanalp, W. T., Bischof, C., John, D., Schulz, M. H., Krishnan, J., Fischer, A., Poluzzi, C., Schaefer, L., Bonauer, A., Zeiher, A. M., & Dimmeler, S. Circulation, 138(22):2545–2558, November, 2018. doi abstract bibtex BACKGROUND: MicroRNAs (miRs) regulate nearly all biological pathways. Because the dysregulation of miRs can lead to disease progression, they are being explored as novel therapeutic targets. However, the cell type-specific effects of miRs in the heart are poorly understood. Thus, we assessed miR target regulation using miR-92a-3p as an example. Inhibition of miR-92a is known to improve endothelial cell function and recovery after acute myocardial infarction. METHODS: miR-92a-3p was inhibited by locked nucleic acid (LNA)-based antimiR (LNA-92a) in mice after myocardial infarction. Expression of regulated genes was evaluated 3 days after myocardial infarction by RNA sequencing of isolated endothelial cells, cardiomyocytes, fibroblasts, and CD45+ hematopoietic cells. RESULTS: LNA-92a depleted miR-92a-3p expression in all cell types and derepressed predicted miR-92a-3p targets in a cell type-specific manner. RNAseq showed endothelial cell-specific regulation of autophagy-related genes. Imaging confirmed increased endothelial cell autophagy in LNA-92a treated relative to control animals. In vitro inhibition of miR-92a-3p augmented EC autophagy, derepressed autophagy-related gene 4a, and increased luciferase activity in autophagy-related gene 4a 3'UTR containing reporters, whereas miR-92a-3p overexpression had the opposite effect. In cardiomyocytes, LNA-92a derepressed metabolism-related genes, notably, the high-density lipoprotein transporter Abca8b. LNA-92a further increased fatty acid uptake and mitochondrial function in cardiomyocytes in vitro. CONCLUSIONS: Our data show that miRs have cell type-specific effects in vivo. Analysis of miR targets in cell subsets disclosed a novel function of miR-92a-3p in endothelial cell autophagy and cardiomyocyte metabolism. Because autophagy is upregulated during ischemia to supply nutrients and cardiomyocyte metabolic-switching improves available substrate utilization, these prosurvival mechanisms may diminish tissue damage.
@article{rogg_analysis_2018,
title = {Analysis of {Cell} {Type}-{Specific} {Effects} of {MicroRNA}-92a {Provides} {Novel} {Insights} {Into} {Target} {Regulation} and {Mechanism} of {Action}},
volume = {138},
issn = {1524-4539},
doi = {10.1161/CIRCULATIONAHA.118.034598},
abstract = {BACKGROUND: MicroRNAs (miRs) regulate nearly all biological pathways. Because the dysregulation of miRs can lead to disease progression, they are being explored as novel therapeutic targets. However, the cell type-specific effects of miRs in the heart are poorly understood. Thus, we assessed miR target regulation using miR-92a-3p as an example. Inhibition of miR-92a is known to improve endothelial cell function and recovery after acute myocardial infarction.
METHODS: miR-92a-3p was inhibited by locked nucleic acid (LNA)-based antimiR (LNA-92a) in mice after myocardial infarction. Expression of regulated genes was evaluated 3 days after myocardial infarction by RNA sequencing of isolated endothelial cells, cardiomyocytes, fibroblasts, and CD45+ hematopoietic cells.
RESULTS: LNA-92a depleted miR-92a-3p expression in all cell types and derepressed predicted miR-92a-3p targets in a cell type-specific manner. RNAseq showed endothelial cell-specific regulation of autophagy-related genes. Imaging confirmed increased endothelial cell autophagy in LNA-92a treated relative to control animals. In vitro inhibition of miR-92a-3p augmented EC autophagy, derepressed autophagy-related gene 4a, and increased luciferase activity in autophagy-related gene 4a 3'UTR containing reporters, whereas miR-92a-3p overexpression had the opposite effect. In cardiomyocytes, LNA-92a derepressed metabolism-related genes, notably, the high-density lipoprotein transporter Abca8b. LNA-92a further increased fatty acid uptake and mitochondrial function in cardiomyocytes in vitro.
CONCLUSIONS: Our data show that miRs have cell type-specific effects in vivo. Analysis of miR targets in cell subsets disclosed a novel function of miR-92a-3p in endothelial cell autophagy and cardiomyocyte metabolism. Because autophagy is upregulated during ischemia to supply nutrients and cardiomyocyte metabolic-switching improves available substrate utilization, these prosurvival mechanisms may diminish tissue damage.},
language = {eng},
number = {22},
journal = {Circulation},
author = {Rogg, Eva-Maria and Abplanalp, Wesley T. and Bischof, Corinne and John, David and Schulz, Marcel H. and Krishnan, Jaya and Fischer, Ariane and Poluzzi, Chiara and Schaefer, Liliana and Bonauer, Angelika and Zeiher, Andreas M. and Dimmeler, Stefanie},
month = nov,
year = {2018},
pmid = {30571345},
keywords = {3' Untranslated Regions, angiogenesis, Animals, Antagomirs, ATP-Binding Cassette Transporters, autophagy, Autophagy, cardiovascular protection, cell signaling, Disease Models, Animal, Human Umbilical Vein Endothelial Cells, Humans, Male, metabolism, Mice, Mice, Inbred C57BL, microRNA, MicroRNAs, myocardial infarction, Myocardial Infarction, Myocytes, Cardiac, Oligonucleotides, Rats},
pages = {2545--2558},
file = {Volltext:/Users/mschulz/Zotero/storage/SITTMUV5/Rogg et al. - 2018 - Analysis of Cell Type-Specific Effects of MicroRNA.pdf:application/pdf},
}
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Thus, we assessed miR target regulation using miR-92a-3p as an example. Inhibition of miR-92a is known to improve endothelial cell function and recovery after acute myocardial infarction. METHODS: miR-92a-3p was inhibited by locked nucleic acid (LNA)-based antimiR (LNA-92a) in mice after myocardial infarction. Expression of regulated genes was evaluated 3 days after myocardial infarction by RNA sequencing of isolated endothelial cells, cardiomyocytes, fibroblasts, and CD45+ hematopoietic cells. RESULTS: LNA-92a depleted miR-92a-3p expression in all cell types and derepressed predicted miR-92a-3p targets in a cell type-specific manner. RNAseq showed endothelial cell-specific regulation of autophagy-related genes. Imaging confirmed increased endothelial cell autophagy in LNA-92a treated relative to control animals. In vitro inhibition of miR-92a-3p augmented EC autophagy, derepressed autophagy-related gene 4a, and increased luciferase activity in autophagy-related gene 4a 3'UTR containing reporters, whereas miR-92a-3p overexpression had the opposite effect. In cardiomyocytes, LNA-92a derepressed metabolism-related genes, notably, the high-density lipoprotein transporter Abca8b. LNA-92a further increased fatty acid uptake and mitochondrial function in cardiomyocytes in vitro. CONCLUSIONS: Our data show that miRs have cell type-specific effects in vivo. Analysis of miR targets in cell subsets disclosed a novel function of miR-92a-3p in endothelial cell autophagy and cardiomyocyte metabolism. Because autophagy is upregulated during ischemia to supply nutrients and cardiomyocyte metabolic-switching improves available substrate utilization, these prosurvival mechanisms may diminish tissue damage.","language":"eng","number":"22","journal":"Circulation","author":[{"propositions":[],"lastnames":["Rogg"],"firstnames":["Eva-Maria"],"suffixes":[]},{"propositions":[],"lastnames":["Abplanalp"],"firstnames":["Wesley","T."],"suffixes":[]},{"propositions":[],"lastnames":["Bischof"],"firstnames":["Corinne"],"suffixes":[]},{"propositions":[],"lastnames":["John"],"firstnames":["David"],"suffixes":[]},{"propositions":[],"lastnames":["Schulz"],"firstnames":["Marcel","H."],"suffixes":[]},{"propositions":[],"lastnames":["Krishnan"],"firstnames":["Jaya"],"suffixes":[]},{"propositions":[],"lastnames":["Fischer"],"firstnames":["Ariane"],"suffixes":[]},{"propositions":[],"lastnames":["Poluzzi"],"firstnames":["Chiara"],"suffixes":[]},{"propositions":[],"lastnames":["Schaefer"],"firstnames":["Liliana"],"suffixes":[]},{"propositions":[],"lastnames":["Bonauer"],"firstnames":["Angelika"],"suffixes":[]},{"propositions":[],"lastnames":["Zeiher"],"firstnames":["Andreas","M."],"suffixes":[]},{"propositions":[],"lastnames":["Dimmeler"],"firstnames":["Stefanie"],"suffixes":[]}],"month":"November","year":"2018","pmid":"30571345","keywords":"3' Untranslated Regions, angiogenesis, Animals, Antagomirs, ATP-Binding Cassette Transporters, autophagy, Autophagy, cardiovascular protection, cell signaling, Disease Models, Animal, Human Umbilical Vein Endothelial Cells, Humans, Male, metabolism, Mice, Mice, Inbred C57BL, microRNA, MicroRNAs, myocardial infarction, Myocardial Infarction, Myocytes, Cardiac, Oligonucleotides, Rats","pages":"2545–2558","file":"Volltext:/Users/mschulz/Zotero/storage/SITTMUV5/Rogg et al. - 2018 - Analysis of Cell Type-Specific Effects of MicroRNA.pdf:application/pdf","bibtex":"@article{rogg_analysis_2018,\n\ttitle = {Analysis of {Cell} {Type}-{Specific} {Effects} of {MicroRNA}-92a {Provides} {Novel} {Insights} {Into} {Target} {Regulation} and {Mechanism} of {Action}},\n\tvolume = {138},\n\tissn = {1524-4539},\n\tdoi = {10.1161/CIRCULATIONAHA.118.034598},\n\tabstract = {BACKGROUND: MicroRNAs (miRs) regulate nearly all biological pathways. Because the dysregulation of miRs can lead to disease progression, they are being explored as novel therapeutic targets. However, the cell type-specific effects of miRs in the heart are poorly understood. Thus, we assessed miR target regulation using miR-92a-3p as an example. Inhibition of miR-92a is known to improve endothelial cell function and recovery after acute myocardial infarction.\nMETHODS: miR-92a-3p was inhibited by locked nucleic acid (LNA)-based antimiR (LNA-92a) in mice after myocardial infarction. Expression of regulated genes was evaluated 3 days after myocardial infarction by RNA sequencing of isolated endothelial cells, cardiomyocytes, fibroblasts, and CD45+ hematopoietic cells.\nRESULTS: LNA-92a depleted miR-92a-3p expression in all cell types and derepressed predicted miR-92a-3p targets in a cell type-specific manner. RNAseq showed endothelial cell-specific regulation of autophagy-related genes. Imaging confirmed increased endothelial cell autophagy in LNA-92a treated relative to control animals. In vitro inhibition of miR-92a-3p augmented EC autophagy, derepressed autophagy-related gene 4a, and increased luciferase activity in autophagy-related gene 4a 3'UTR containing reporters, whereas miR-92a-3p overexpression had the opposite effect. In cardiomyocytes, LNA-92a derepressed metabolism-related genes, notably, the high-density lipoprotein transporter Abca8b. LNA-92a further increased fatty acid uptake and mitochondrial function in cardiomyocytes in vitro.\nCONCLUSIONS: Our data show that miRs have cell type-specific effects in vivo. Analysis of miR targets in cell subsets disclosed a novel function of miR-92a-3p in endothelial cell autophagy and cardiomyocyte metabolism. Because autophagy is upregulated during ischemia to supply nutrients and cardiomyocyte metabolic-switching improves available substrate utilization, these prosurvival mechanisms may diminish tissue damage.},\n\tlanguage = {eng},\n\tnumber = {22},\n\tjournal = {Circulation},\n\tauthor = {Rogg, Eva-Maria and Abplanalp, Wesley T. and Bischof, Corinne and John, David and Schulz, Marcel H. and Krishnan, Jaya and Fischer, Ariane and Poluzzi, Chiara and Schaefer, Liliana and Bonauer, Angelika and Zeiher, Andreas M. and Dimmeler, Stefanie},\n\tmonth = nov,\n\tyear = {2018},\n\tpmid = {30571345},\n\tkeywords = {3' Untranslated Regions, angiogenesis, Animals, Antagomirs, ATP-Binding Cassette Transporters, autophagy, Autophagy, cardiovascular protection, cell signaling, Disease Models, Animal, Human Umbilical Vein Endothelial Cells, Humans, Male, metabolism, Mice, Mice, Inbred C57BL, microRNA, MicroRNAs, myocardial infarction, Myocardial Infarction, Myocytes, Cardiac, Oligonucleotides, Rats},\n\tpages = {2545--2558},\n\tfile = {Volltext:/Users/mschulz/Zotero/storage/SITTMUV5/Rogg et al. - 2018 - Analysis of Cell Type-Specific Effects of MicroRNA.pdf:application/pdf},\n}\n\n","author_short":["Rogg, E.","Abplanalp, W. 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