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MicroRNA-532-3p regulates mitochondrial fission through targeting apoptosis repressor with caspase recruitment domain in doxorubicin cardiotoxicity.

Wang JX, Zhang XJ, Feng C, Sun T, Wang K, Wang Y, Zhou LY, Li PF - Cell Death Dis (2015)

Bottom Line: DOX-induced mitochondrial fission required the activity of dynamin-related protein 1 (Drp1).In elucidating the molecular mechanism by which ARC was downregulated upon DOX treatment, miR-532-3p was found to directly target ARC and participated in DOX-induced mitochondrial fission and apoptosis.MiR-532-3p was not involved in DOX-induced apoptosis in cancer cells.

View Article: PubMed Central - PubMed

Affiliation: 1] National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China [2] Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China.

ABSTRACT
Doxorubicin (DOX) is a wide-spectrum antitumor drug, but its clinical application is limited by its cardiotoxicity. However, the mechanisms underlying DOX-induced cardiomyopathy remain mostly unclear. Here we observed that apoptosis repressor with caspase recruitment domain (ARC) was downregulated in mouse heart and cardiomyocytes upon DOX treatment. Furthermore, enforced expression of ARC attenuated DOX-induced cardiomyocyte mitochondrial fission and apoptosis. ARC transgenic mice demonstrated reduced cardiotoxicity upon DOX administration. DOX-induced mitochondrial fission required the activity of dynamin-related protein 1 (Drp1). In elucidating the molecular mechanism by which ARC was downregulated upon DOX treatment, miR-532-3p was found to directly target ARC and participated in DOX-induced mitochondrial fission and apoptosis. MiR-532-3p was not involved in DOX-induced apoptosis in cancer cells. Taken together, these findings provide novel evidence that miR-532-3p and ARC constitute an antiapoptotic pathway that regulates DOX cardiotoxicity. Therefore, the development of new therapeutic strategies based on ARC and miR-532-3p is promising for overcoming the cardiotoxicity of chemotherapy for cancer therapy.

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MiR-532-3p regulates mitochondrial fission and apoptosis by targeting ARC. (a and b) MiR-532-3p-increased sensitivity to DOX treatment was abolished by ARC. Mitochondrial fission (a) and cell death (b) were measured in neonatal rat cardiomyocytes upon 0.2 μM DOX treatment. (c and d) MiR-532-3p antagomir-attenuated DOX treatment was abolished by endogenous ARC knockdown. Mitochondrial fission (c) and cell death (d) were measured in cardiomyocytes upon 2 μM DOX treatment. (e) Enforced expression of miR-532-3p did not affect cell death in neonatal mouse cardiomyocytes isolated from ARC Tg mice upon DOX (0.2 μM) treatment. Data are expressed as the mean±S.D., n=3. *P<0.05
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fig6: MiR-532-3p regulates mitochondrial fission and apoptosis by targeting ARC. (a and b) MiR-532-3p-increased sensitivity to DOX treatment was abolished by ARC. Mitochondrial fission (a) and cell death (b) were measured in neonatal rat cardiomyocytes upon 0.2 μM DOX treatment. (c and d) MiR-532-3p antagomir-attenuated DOX treatment was abolished by endogenous ARC knockdown. Mitochondrial fission (c) and cell death (d) were measured in cardiomyocytes upon 2 μM DOX treatment. (e) Enforced expression of miR-532-3p did not affect cell death in neonatal mouse cardiomyocytes isolated from ARC Tg mice upon DOX (0.2 μM) treatment. Data are expressed as the mean±S.D., n=3. *P<0.05

Mentions: We explored how miR-532-3p exerts its effects on the mitochondrial network. As miR-532-3p is able to suppress ARC expression, we wondered whether miR-532-3p regulated DOX sensitivity in cardiomyocytes by targeting ARC. Overexpression of miR-532-3p sensitized low-dose DOX-induced mitochondrial fission and cell death. Enforced expression of ARC showed a strong inhibitory effect on mitochondrial fission (Figure 6a) and cell death (Figure 6b) in the presence of miR-532-3p. Reduced endogenous expression level of miR-532-3p inhibited DOX-induced mitochondrial fission and cell death. Knockdown of ARC attenuated this inhibitory effect on mitochondrial fission (Figure 6c) and cell death (Figure 6d) in the presence of miR-532-3p antagomir. Then we attempted to investigate the influence of miR-532-3p on cell susceptibility to neonatal mouse cardiomyocytes isolated from ARC transgenic mice. Overexpression of miR-532-3p had no significant effect on cell death in response to the low-dose DOX (0.2 μM) treatment (Figure 6e). These data suggest that miR-532-3p targets ARC in the cascades of mitochondrial fission and apoptosis during DOX cardiotoxicity.


MicroRNA-532-3p regulates mitochondrial fission through targeting apoptosis repressor with caspase recruitment domain in doxorubicin cardiotoxicity.

Wang JX, Zhang XJ, Feng C, Sun T, Wang K, Wang Y, Zhou LY, Li PF - Cell Death Dis (2015)

MiR-532-3p regulates mitochondrial fission and apoptosis by targeting ARC. (a and b) MiR-532-3p-increased sensitivity to DOX treatment was abolished by ARC. Mitochondrial fission (a) and cell death (b) were measured in neonatal rat cardiomyocytes upon 0.2 μM DOX treatment. (c and d) MiR-532-3p antagomir-attenuated DOX treatment was abolished by endogenous ARC knockdown. Mitochondrial fission (c) and cell death (d) were measured in cardiomyocytes upon 2 μM DOX treatment. (e) Enforced expression of miR-532-3p did not affect cell death in neonatal mouse cardiomyocytes isolated from ARC Tg mice upon DOX (0.2 μM) treatment. Data are expressed as the mean±S.D., n=3. *P<0.05
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385919&req=5

fig6: MiR-532-3p regulates mitochondrial fission and apoptosis by targeting ARC. (a and b) MiR-532-3p-increased sensitivity to DOX treatment was abolished by ARC. Mitochondrial fission (a) and cell death (b) were measured in neonatal rat cardiomyocytes upon 0.2 μM DOX treatment. (c and d) MiR-532-3p antagomir-attenuated DOX treatment was abolished by endogenous ARC knockdown. Mitochondrial fission (c) and cell death (d) were measured in cardiomyocytes upon 2 μM DOX treatment. (e) Enforced expression of miR-532-3p did not affect cell death in neonatal mouse cardiomyocytes isolated from ARC Tg mice upon DOX (0.2 μM) treatment. Data are expressed as the mean±S.D., n=3. *P<0.05
Mentions: We explored how miR-532-3p exerts its effects on the mitochondrial network. As miR-532-3p is able to suppress ARC expression, we wondered whether miR-532-3p regulated DOX sensitivity in cardiomyocytes by targeting ARC. Overexpression of miR-532-3p sensitized low-dose DOX-induced mitochondrial fission and cell death. Enforced expression of ARC showed a strong inhibitory effect on mitochondrial fission (Figure 6a) and cell death (Figure 6b) in the presence of miR-532-3p. Reduced endogenous expression level of miR-532-3p inhibited DOX-induced mitochondrial fission and cell death. Knockdown of ARC attenuated this inhibitory effect on mitochondrial fission (Figure 6c) and cell death (Figure 6d) in the presence of miR-532-3p antagomir. Then we attempted to investigate the influence of miR-532-3p on cell susceptibility to neonatal mouse cardiomyocytes isolated from ARC transgenic mice. Overexpression of miR-532-3p had no significant effect on cell death in response to the low-dose DOX (0.2 μM) treatment (Figure 6e). These data suggest that miR-532-3p targets ARC in the cascades of mitochondrial fission and apoptosis during DOX cardiotoxicity.

Bottom Line: DOX-induced mitochondrial fission required the activity of dynamin-related protein 1 (Drp1).In elucidating the molecular mechanism by which ARC was downregulated upon DOX treatment, miR-532-3p was found to directly target ARC and participated in DOX-induced mitochondrial fission and apoptosis.MiR-532-3p was not involved in DOX-induced apoptosis in cancer cells.

View Article: PubMed Central - PubMed

Affiliation: 1] National Key Laboratory of Biomembrane and Membrane Biotechnology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China [2] Institute for Translational Medicine, College of Medicine, Qingdao University, Qingdao, China.

ABSTRACT
Doxorubicin (DOX) is a wide-spectrum antitumor drug, but its clinical application is limited by its cardiotoxicity. However, the mechanisms underlying DOX-induced cardiomyopathy remain mostly unclear. Here we observed that apoptosis repressor with caspase recruitment domain (ARC) was downregulated in mouse heart and cardiomyocytes upon DOX treatment. Furthermore, enforced expression of ARC attenuated DOX-induced cardiomyocyte mitochondrial fission and apoptosis. ARC transgenic mice demonstrated reduced cardiotoxicity upon DOX administration. DOX-induced mitochondrial fission required the activity of dynamin-related protein 1 (Drp1). In elucidating the molecular mechanism by which ARC was downregulated upon DOX treatment, miR-532-3p was found to directly target ARC and participated in DOX-induced mitochondrial fission and apoptosis. MiR-532-3p was not involved in DOX-induced apoptosis in cancer cells. Taken together, these findings provide novel evidence that miR-532-3p and ARC constitute an antiapoptotic pathway that regulates DOX cardiotoxicity. Therefore, the development of new therapeutic strategies based on ARC and miR-532-3p is promising for overcoming the cardiotoxicity of chemotherapy for cancer therapy.

Show MeSH
Related in: MedlinePlus