MicroRNA therapy confers anti-senescent effects on doxorubicin-related cardiotoxicity by intracellular and paracrine signaling

Abstract

Doxorubicin (Dox), an important anthracycline, is a potent anticancer agent that is used for treating solid tumors and hematologic malignancies. However, its clinical use is hampered by cardiac cardiotoxicity. This study aimed to investigate the cardioprotective potential of miR-199a-3p. Continuous Dox treatment not only markedly induced cardiomyocyte senescence but also resulted in a growing number of senescence-associated secretory phenotype (SASP) cardiomyocytes, frequently leading to heart senescence. This study showed that miR-199a-3p was downregulated in cardiomyocytes when exposed to Dox. The cardiac-specific overexpression of miR-199a-3p promoted cell cycle re-entry and cell proliferation, resulting in relief from cardiac senescence. Also, the elevation of miR-199a-3p inhibited the generation of SASP, thus, hampering the spread of senescence. In cardiomyocytes, the modulation of miR-199a-3p changed the levels of senescence-related protein GATA4. The ectopic expression of GATA4 blunted the anti-senescence effect of miR-199a-3p. Together, the data supported a role for miR-199a-3p during Dox cardiotoxicity. The elevation of miR-199a-3p might provide a dual therapeutic advantage in Dox cardiotoxicity therapy by simultaneously preventing cardiac senescence and reducing the spread of senescence.

The Potential of Senescence as a Target for Developing Anticancer Therapy

“…Doxorubicin increased the number of senescence-associated secretory phenotypes but decreased the expression of miR-199a-3p in cardiomyocytes [ 130 ]. The overexpression of miR-199a-3p inhibited SASP production and the spread of senescence by decreasing the expression of GATA-4 in cardiomyocytes [ 130 ]. This suggests that an miR-199a-3p mimic could be developed as an anticancer drug owing to its role in regulating SASP production.…”

MicroRNAs in doxorubicin-induced cardiotoxicity: The DNA damage response

“…Vacchi-Suzzi et al described downregulation in rat hearts rather than upregulation ( Vacchi-Suzzi et al, 2012 ). Meanwhile, miR-199a-3p is another miRNA that directly targets GATA-4, but its level was attenuated in cardiomyocytes by DOX treatment rather than increased ( Xia et al, 2021 ). miR-199a-3p attenuated cardiomyocytes’ senescence and promoted cell proliferation, indicating a potential therapeutic effect in DIC ( Xia et al, 2021 ).…”

Non-coding RNAs in cancer therapy-induced cardiotoxicity: Mechanisms, biomarkers, and treatments

“…According to a recent study, miR-199a-3p not only attenuated DOX-induced senescence in cardiomyocytes but also reduced the spread of senescence ( 15 ). GATA4 is a critical factor regulating programmed senescence and injury-induced senescence, and miR-199a-3p reduces its translation by binding straightly to its 3′-UTR, which has an antiaging impact.…”