Divergent Effects of miR‐181 Family Members on Myocardial Function Through Protective Cytosolic and Detrimental Mitochondrial microRNA Targets
Background MicroRNA (miRNA) is a type of noncoding RNA that can repress the expression of target genes through posttranscriptional regulation. In addition to numerous physiologic roles for miRNAs, they play an important role in pathophysiologic processes affecting cardiovascular health. Previously,...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2017-03-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| Subjects: | |
| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.116.004694 |
| _version_ | 1828405598117429248 |
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| author | Samarjit Das Mark Kohr Brittany Dunkerly‐Eyring Dong I. Lee Djahida Bedja Oliver A. Kent Anthony K. L. Leung Jorge Henao‐Mejia Richard A. Flavell Charles Steenbergen |
| author_facet | Samarjit Das Mark Kohr Brittany Dunkerly‐Eyring Dong I. Lee Djahida Bedja Oliver A. Kent Anthony K. L. Leung Jorge Henao‐Mejia Richard A. Flavell Charles Steenbergen |
| author_sort | Samarjit Das |
| collection | DOAJ |
| description | Background MicroRNA (miRNA) is a type of noncoding RNA that can repress the expression of target genes through posttranscriptional regulation. In addition to numerous physiologic roles for miRNAs, they play an important role in pathophysiologic processes affecting cardiovascular health. Previously, we reported that nuclear encoded microRNA (miR‐181c) is present in heart mitochondria, and importantly, its overexpression affects mitochondrial function by regulating mitochondrial gene expression. Methods and Results To investigate further how the miR‐181 family affects the heart, we suppressed miR‐181 using a miR‐181‐sponge containing 10 repeated complementary miR‐181 “seed” sequences and generated a set of H9c2 cells, a cell line derived from rat myoblast, by stably expressing either a scrambled or miR‐181‐sponge sequence. Sponge‐H9c2 cells showed a decrease in reactive oxygen species production and reduced basal mitochondrial respiration and protection against doxorubicin‐induced oxidative stress. We also found that miR‐181a/b targets phosphatase and tensin homolog (PTEN), and the sponge‐expressing stable cells had increased PTEN activity and decreased PI3K signaling. In addition, we have used miR‐181a/b−/− and miR‐181c/d−/− knockout mice and subjected them to ischemia‐reperfusion injury. Our results suggest divergent effects of different miR‐181 family members: miR‐181a/b targets PTEN in the cytosol, resulting in an increase in infarct size in miR‐181a/b−/− mice due to increased PTEN signaling, whereas miR‐181c targets mt‐COX1 in the mitochondria, resulting in decreased infarct size in miR‐181c/d−/− mice. Conclusions The miR‐181 family alters the myocardial response to oxidative stress, notably with detrimental effects by targeting mt‐COX1 (miR‐181c) or with protection by targeting PTEN (miR‐181a/b). |
| first_indexed | 2024-12-10T10:56:11Z |
| format | Article |
| id | doaj.art-a94e41b1299f4996baf2810b15e2f3b0 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-10T10:56:11Z |
| publishDate | 2017-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-a94e41b1299f4996baf2810b15e2f3b02022-12-22T01:51:52ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802017-03-016310.1161/JAHA.116.004694Divergent Effects of miR‐181 Family Members on Myocardial Function Through Protective Cytosolic and Detrimental Mitochondrial microRNA TargetsSamarjit Das0Mark Kohr1Brittany Dunkerly‐Eyring2Dong I. Lee3Djahida Bedja4Oliver A. Kent5Anthony K. L. Leung6Jorge Henao‐Mejia7Richard A. Flavell8Charles Steenbergen9Department of Pathology Johns Hopkins School of Medicine Baltimore MDDepartment of Environmental Health and Engineering Bloomberg School of Public Health Johns Hopkins University Baltimore MDDepartment of Pathology Johns Hopkins School of Medicine Baltimore MDDepartment of Cardiology Johns Hopkins School of Medicine Baltimore MDDepartment of Cardiology Johns Hopkins School of Medicine Baltimore MDPrincess Margaret Cancer Centre University of Toronto Ontario CanadaDepartment of Biochemistry and Molecular Biology Bloomberg School of Public Health Johns Hopkins University Baltimore MDDepartment of Pathology and Laboratory Medicine Perelman School of Medicine University of Pennsylvania Philadelphia PADepartment of Immunobiology Yale University School of Medicine New Haven CTDepartment of Pathology Johns Hopkins School of Medicine Baltimore MDBackground MicroRNA (miRNA) is a type of noncoding RNA that can repress the expression of target genes through posttranscriptional regulation. In addition to numerous physiologic roles for miRNAs, they play an important role in pathophysiologic processes affecting cardiovascular health. Previously, we reported that nuclear encoded microRNA (miR‐181c) is present in heart mitochondria, and importantly, its overexpression affects mitochondrial function by regulating mitochondrial gene expression. Methods and Results To investigate further how the miR‐181 family affects the heart, we suppressed miR‐181 using a miR‐181‐sponge containing 10 repeated complementary miR‐181 “seed” sequences and generated a set of H9c2 cells, a cell line derived from rat myoblast, by stably expressing either a scrambled or miR‐181‐sponge sequence. Sponge‐H9c2 cells showed a decrease in reactive oxygen species production and reduced basal mitochondrial respiration and protection against doxorubicin‐induced oxidative stress. We also found that miR‐181a/b targets phosphatase and tensin homolog (PTEN), and the sponge‐expressing stable cells had increased PTEN activity and decreased PI3K signaling. In addition, we have used miR‐181a/b−/− and miR‐181c/d−/− knockout mice and subjected them to ischemia‐reperfusion injury. Our results suggest divergent effects of different miR‐181 family members: miR‐181a/b targets PTEN in the cytosol, resulting in an increase in infarct size in miR‐181a/b−/− mice due to increased PTEN signaling, whereas miR‐181c targets mt‐COX1 in the mitochondria, resulting in decreased infarct size in miR‐181c/d−/− mice. Conclusions The miR‐181 family alters the myocardial response to oxidative stress, notably with detrimental effects by targeting mt‐COX1 (miR‐181c) or with protection by targeting PTEN (miR‐181a/b).https://www.ahajournals.org/doi/10.1161/JAHA.116.004694microRNAmiR‐181mitochondriamitochondrial miRNAmitochondrial respiratory complex IVmt‐COX1 |
| spellingShingle | Samarjit Das Mark Kohr Brittany Dunkerly‐Eyring Dong I. Lee Djahida Bedja Oliver A. Kent Anthony K. L. Leung Jorge Henao‐Mejia Richard A. Flavell Charles Steenbergen Divergent Effects of miR‐181 Family Members on Myocardial Function Through Protective Cytosolic and Detrimental Mitochondrial microRNA Targets Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease microRNA miR‐181 mitochondria mitochondrial miRNA mitochondrial respiratory complex IV mt‐COX1 |
| title | Divergent Effects of miR‐181 Family Members on Myocardial Function Through Protective Cytosolic and Detrimental Mitochondrial microRNA Targets |
| title_full | Divergent Effects of miR‐181 Family Members on Myocardial Function Through Protective Cytosolic and Detrimental Mitochondrial microRNA Targets |
| title_fullStr | Divergent Effects of miR‐181 Family Members on Myocardial Function Through Protective Cytosolic and Detrimental Mitochondrial microRNA Targets |
| title_full_unstemmed | Divergent Effects of miR‐181 Family Members on Myocardial Function Through Protective Cytosolic and Detrimental Mitochondrial microRNA Targets |
| title_short | Divergent Effects of miR‐181 Family Members on Myocardial Function Through Protective Cytosolic and Detrimental Mitochondrial microRNA Targets |
| title_sort | divergent effects of mir 181 family members on myocardial function through protective cytosolic and detrimental mitochondrial microrna targets |
| topic | microRNA miR‐181 mitochondria mitochondrial miRNA mitochondrial respiratory complex IV mt‐COX1 |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.116.004694 |
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