Abstract
Numerous cardiac diseases, including myocardial infarction (MI) and chronic heart failure, have been associated with cardiomyocyte apoptosis. Promoting cell survival by inhibiting apoptosis is one of the effective strategies to attenuate cardiac dysfunction caused by cardiomyocyte loss. miR-24 has been shown as an anti-apoptotic microRNA in various animal models. In vivo delivery of miR-24 into a mouse MI model suppressed cardiac cell death, attenuated infarct size, and rescued cardiac dysfunction. However, the molecular pathway by which miR-24 inhibits cardiomyocyte apoptosis is not known. Here we found that miR-24 negatively regulates mouse primary cadiomyocyte cell death through functioning in the intrinsic apoptotic pathways. In ER-mediated intrinsic pathway, miR-24 genetically interacts with the CEBP homologous gene CHOP as knocking down of CHOP partially attenuated the induced apoptosis by miR-24 inhibition. In mitochondria–involved intrinsic pathway, miR-24 inhibits the initiation of apoptosis through suppression of Cytochrome C release and Bax translocation from cytosol to mitochondria. These results provide mechanistic insights into the miR-24 mediated anti-apoptotic effects in murine cardiomyocytes.
Highlights
Cardiac disease is the leading cause of death and disability in the developed countries
We found that introduction of miR-24 significantly attenuated the increased percentage of AnnexinV+propidium iodide (PI)- early apoptotic cells induced by camptothecin (18% to 12%, p,0.05), but not by Fas (18% to 17%, p.0.05) (Fig. 1A and B)
We showed that miR-24 modulated intrinsic apoptosis by interacting with CHOP-mediated endoplasmic reticulum (ER) pathways and by inhibiting cytochrome C release, and Bax translocation from cytosol to mitochondria. miR-24 is up-regulated upon cardiac stress in animal models and in humans [41] and may be mediating a compensatory response under cardiac stress
Summary
Cardiac disease is the leading cause of death and disability in the developed countries. In the US over five million patients suffer from progressive cardiac dysfunction, known as heart failure. A variety of animal and human studies have demonstrated that apoptosis (programmed cell death) contributes significantly to cardiomyocyte loss during the development and progression of heart failure [1,2]. Because cardiomyocytes are terminally differentiated and have little potential for division, preventing cell death has important implications in the treatment of cardiovascular disease [3]. Activation of caspases is central to apoptosis and can be initiated by any of three distinct mechanisms: (1) ligand binding to death receptors, (2) release of Cytochrome C from mitochondria, and (3) stress to the endoplasmic reticulum (ER) [9,10,11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
