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A carvedilol-responsive microRNA, miR-125b-5p protects the heart from acute myocardial infarction by repressing pro-apoptotic bak1 and klf13 in cardiomyocytes
- Source :
- Journal of Molecular and Cellular Cardiology. 114:72-82
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- 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.
- Subjects :
- 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
Subjects
Details
- ISSN :
- 00222828
- Volume :
- 114
- Database :
- OpenAIRE
- Journal :
- Journal of Molecular and Cellular Cardiology
- Accession number :
- edsair.doi.dedup.....85bd3722fdd2afd20c6cc678fd38e76b