A carvedilol-responsive microRNA, miR-125b-5p protects the heart from acute myocardial infarction by repressing pro-apoptotic bak1 and klf13 in cardiomyocytes
| Autor: | Ahmed S. Bayoumi, Neal L. Weintraub, Tatsuya Aonuma, Il-man Kim, Kyoung-mi Park, Huabo Su, Yao Liang Tang, Jian Peng Teoh, Yongchao Wang |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Cardiac function curve medicine.medical_specialty Cardiotonic Agents Kruppel-Like Transcription Factors Myocardial Infarction Apoptosis Cell Cycle Proteins Biology Models Biological Article Cell Line Rats Sprague-Dawley Ventricular Dysfunction Left 03 medical and health sciences Internal medicine microRNA medicine Animals Myocytes Cardiac Myocardial infarction Molecular Biology Carvedilol Cardioprotection Ischemic cardiomyopathy Dilated cardiomyopathy medicine.disease Mice Inbred C57BL Repressor Proteins MicroRNAs bcl-2 Homologous Antagonist-Killer Protein 030104 developmental biology Endocrinology Gene Knockdown Techniques Heart failure Cancer research Cardiology and Cardiovascular Medicine medicine.drug |
| Zdroj: | Journal of Molecular and Cellular Cardiology. 114:72-82 |
| ISSN: | 0022-2828 |
| Popis: | Background Cardiac injury is accompanied by dynamic changes in the expression of microRNAs (miRs), small non-coding RNAs that post-transcriptionally regulate target genes. MiR-125b-5p is downregulated in patients with end-stage dilated and ischemic cardiomyopathy, and has been proposed as a biomarker of heart failure. We previously reported that the β-blocker carvedilol promotes cardioprotection via β-arrestin-biased agonism of β1-adrenergic receptor while stimulating miR-125b-5p processing in the mouse heart. We hypothesize that β1-adrenergic receptor/β-arrestin1-responsive miR-125b-5p confers the improvement of cardiac function and structure after acute myocardial infarction. Methods and results Using cultured cardiomyocyte (CM) and in vivo approaches, we show that miR-125b-5p is an ischemic stress-responsive protector against CM apoptosis. CMs lacking miR-125b-5p exhibit increased susceptibility to stress-induced apoptosis, while CMs overexpressing miR-125b-5p have increased phospho-AKT pro-survival signaling. Moreover, we demonstrate that loss-of-function of miR-125b-5p in the mouse heart causes abnormalities in cardiac structure and function after acute myocardial infarction. Mechanistically, the improvement of cardiac function and structure elicited by miR-125b-5p is in part attributed to repression of the pro-apoptotic genes Bak1 and Klf13 in CMs. Conclusions In conclusion, these findings reveal a pivotal role for miR-125b-5p in regulating CM survival during acute myocardial infarction. |
| Databáze: | OpenAIRE |
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