A carvedilol-responsive microRNA, miR-125b-5p protects the heart from acute myocardial infarction by repressing pro-apoptotic bak1 and klf13 in cardiomyocytes

Ahmed S. Bayoumi, Kyoung mi Park, Yongchao Wang, Jian peng Teoh, Tatsuya Aonuma, Yao Liang Tang, Huabo Su, Neal Lee Weintraub, Il-man Kim

Research output: Contribution to journalArticle

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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.

LanguageEnglish (US)
Pages72-82
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume114
DOIs
StatePublished - Jan 1 2018

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MicroRNAs
Cardiac Myocytes
Myocardial Infarction
Apoptosis
Small Untranslated RNA
Congenital Heart Defects
Receptors, Adrenergic, beta
Dilated Cardiomyopathy
Adrenergic Receptors
Genes
Down-Regulation
Heart Failure
Biomarkers
Survival
Wounds and Injuries
carvedilol

Keywords

  • Apoptotic genes
  • Biased G protein-coupled receptor signaling
  • Cardioprotection
  • MicroRNAs
  • β-arrestin

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

A carvedilol-responsive microRNA, miR-125b-5p protects the heart from acute myocardial infarction by repressing pro-apoptotic bak1 and klf13 in cardiomyocytes. / Bayoumi, Ahmed S.; Park, Kyoung mi; Wang, Yongchao; Teoh, Jian peng; Aonuma, Tatsuya; Tang, Yao Liang; Su, Huabo; Weintraub, Neal Lee; Kim, Il-man.

In: Journal of Molecular and Cellular Cardiology, Vol. 114, 01.01.2018, p. 72-82.

Research output: Contribution to journalArticle

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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.",
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author = "Bayoumi, {Ahmed S.} and Park, {Kyoung mi} and Yongchao Wang and Teoh, {Jian peng} and Tatsuya Aonuma and Tang, {Yao Liang} and Huabo Su and Weintraub, {Neal Lee} and Il-man Kim",
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AU - Bayoumi, Ahmed S.

AU - Park, Kyoung mi

AU - Wang, Yongchao

AU - Teoh, Jian peng

AU - Aonuma, Tatsuya

AU - Tang, Yao Liang

AU - Su, Huabo

AU - Weintraub, Neal Lee

AU - Kim, Il-man

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N2 - 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.

AB - 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.

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