| Autor: |
Banavath HN; Department of Pathology Johns Hopkins School of Medicine Baltimore MD., Roman B; Department of Pathology Johns Hopkins School of Medicine Baltimore MD., Mackowski N; Department of Environmental Health and Engineering Johns Hopkins Bloomberg School of Public Health Baltimore MD., Biswas D; Department of Pathology Johns Hopkins School of Medicine Baltimore MD., Afzal J; Department of Medicine UCSF School of Medicine San Francisco CA., Nomura Y; Division of Cardiac Surgery Department of Surgery Johns Hopkins School of Medicine Baltimore MD., Solhjoo S; Department of Pathology Johns Hopkins School of Medicine Baltimore MD.; Division of Cardiology Department of Medicine Johns Hopkins School of Medicine Baltimore MD., O'Rourke B; Division of Cardiology Department of Medicine Johns Hopkins School of Medicine Baltimore MD., Kohr M; Department of Environmental Health and Engineering Johns Hopkins Bloomberg School of Public Health Baltimore MD., Murphy E; Cardiac Physiology Section National Heart, Lung, and Blood Institute NIH Bethesda MD., Steenbergen C; Department of Pathology Johns Hopkins School of Medicine Baltimore MD., Das S; Department of Pathology Johns Hopkins School of Medicine Baltimore MD.; Department of Anesthesiology & Critical Care Medicine Johns Hopkins School of Medicine Baltimore MD. |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of the American Heart Association [J Am Heart Assoc] 2019 Dec 17; Vol. 8 (24), pp. e012919. Date of Electronic Publication: 2019 Dec 05. |
| DOI: |
10.1161/JAHA.119.012919 |
| Abstrakt: |
Background Translocation of miR-181c into cardiac mitochondria downregulates the mitochondrial gene, mt-COX1. miR-181c/d -/- hearts experience less oxidative stress during ischemia/reperfusion (I/R) and are protected against I/R injury. Additionally, miR-181c overexpression can increase mitochondrial matrix Ca 2+ ([Ca 2+ ] m ), but the mechanism by which miR-181c regulates [Ca 2+ ] m is unknown. Methods and Results By RNA sequencing and analysis, here we show that hearts from miR-181c/d -/- mice overexpress nuclear-encoded Ca 2+ regulatory and metabolic pathway genes, suggesting that alterations in miR-181c and mt-COX1 perturb mitochondria-to-nucleus retrograde signaling and [Ca 2+ ] m regulation. Quantitative polymerase chain reaction validation of transcription factors that are known to initiate retrograde signaling revealed significantly higher Sp1 (specificity protein) expression in the miR-181c/d -/- hearts. Furthermore, an association of Sp1 with the promoter region of MICU1 was confirmed by chromatin immunoprecipitation-quantitative polymerase chain reaction and higher expression of MICU1 was found in the miR-181c/d -/- hearts. Conversely, downregulation of Sp1 by small interfering RNA decreased MICU1 expression in neonatal mouse ventricular myocytes. Changes in PDH activity provided evidence for a change in [Ca 2+ ] m via the miR-181c/MICU1 axis. Moreover, this mechanism was implicated in the pathology of I/R injury. When MICU1 was knocked down in the miR-181c/d -/- heart by lentiviral expression of a short-hairpin RNA against MICU1, cardioprotective effects against I/R injury were abrogated. Furthermore, using an in vitro I/R model in miR-181c/d -/- neonatal mouse ventricular myocytes, we confirmed the contribution of both Sp1 and MICU1 in ischemic injury. Conclusions miR-181c regulates mt-COX1, which in turn regulates MICU1 expression through the Sp1-mediated mitochondria-to-nucleus retrograde pathway. Loss of miR-181c can protect the heart from I/R injury by modulating [Ca 2+ ] m through the upregulation of MICU1. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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