A carvedilol-responsive microRNA, miR-125b-5p protects the heart from acute myocardial infarction by repressing pro-apoptotic bak1 and klf13 in cardiomyocytes
Graphical abstract
Section snippets
Subject codes
Non-coding RNAs
Cell signaling/signal transduction
Receptor pharmacology
Heart failure-basic studies
Animal study approval
Eight to 12-week-old C57BL/6 wild-type (WT) mice and 1- to 2-day-old Sprague-Dawley rats were used for this study. Research with animals carried out for this study was performed according to approved protocols and animal welfare regulations of Augusta University's Institutional IACUC Committees. All animal procedures were performed in accordance with NIH guidelines. Neonatal rats were euthanized by decapitation under anesthesia for CM isolation, and mice were euthanized by thoracotomy with 1–4%
In vivo knockdown of miR-125b-5p results in enhanced post-AMI mortality and left ventricular dysfunction
To investigate the role of miR-125b-5p in experimental MI, we intramyocardially injected LNA™-antimiR-125b-5p into WT mice immediately after LAD occlusion or sham surgery. First, we demonstrated efficacy of the antimiR-125b-5p by showing that the level of miR-125b-5p was reduced, for instance, by ~ 75% after 7 days compared with anti-miR controls in both the sham and MI groups (Fig. 1A and data not shown). We further showed that the hearts of antimiR-125b-5p-injected mice at baseline were
Discussion
Here, we identify miR-125b-5p as an ischemic stress-responsive protector against CM apoptosis both in vivo and in vitro. Knockdown of miR-125b-5p renders mice more sensitive to ischemic injury, as evidenced by increased cardiac apoptosis and fibrosis as well as impairment of ventricular function following AMI. Mechanistically, we determined that miR-125b-5p targets pro-apoptotic bak1 and klf13 to elicit its protective effects. CMs deficient in miR-125b-5p exhibit increased sensitivity to
Conclusions
Our results suggest that miR-125b-5p protects the heart against AMI by blunting CM death in response to injury in part through its repression of bak1 and klf13 (Fig. 8D). Although additional mechanistic studies concentrating on miR-125b-5p in different injury models and in other cardiac cell types are needed, our data nevertheless suggest that boosting miR-125b-5p levels to attenuate CM death may provide therapeutic benefits given that downregulation of miR-125b-5p is associated with ischemic
Sources of funding
This work was supported by American Heart Association Predoctoral Fellowship 16PRE30210016 to Jian-peng Teoh, National Institutes of Health R01 HL086555 to Yaoliang Tang, National Institutes of Health R01 HL124248 to Huabo Su, National Institutes of Health R01 HL134354 and AR070029 to Yaoliang Tang and Neal L. Weintraub, National Institutes of Health R01 HL112640 and HL126949 to Neal L. Weintraub, and American Physiological Society (APHYS00008) Shih-Chun Wang Young Investigator Award, American
Disclosures
The authors declare no conflict of interest.
Acknowledgements
We thank Drs. Ruth Caldwell, Zsolt Bagi and Zheng Dong for sharing their equipment, and Dr. Zuzana Bologna for excellent technical assistance.
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Cited by (0)
- 1
Present address: Washington University, Saint Louis, MO, USA.
- 2
Present address: University of Kentucky, Lexington, KY, USA.