Abstract
Doxorubicin (DOX) cardiotoxicity is a life-threatening side effect that leads to a poor prognosis in patients receiving chemotherapy. We investigated the role of miR-22 in doxorubicin-induced cardiomyopathy and the underlying mechanism in vivo and in vitro. Specifically, we designed loss-of-function and gain-of-function experiments to identify the role of miR-22 in doxorubicin-induced cardiomyopathy. Our data suggested that inhibiting miR-22 alleviated cardiac fibrosis and cardiac dysfunction induced by doxorubicin. In addition, inhibiting miR-22 mitigated mitochondrial dysfunction through the sirt1/PGC-1α pathway. Knocking out miR-22 enhanced mitochondrial biogenesis, as evidenced by increased PGC-1α, TFAM, and NRF-1 expression in vivo. Furthermore, knocking out miR-22 rescued mitophagy, which was confirmed by increased expression of PINK1 and parkin and by the colocalization of LC3 and mitochondria. These protective effects were abolished by overexpressing miR-22. In conclusion, miR-22 may represent a new target to alleviate cardiac dysfunction in doxorubicin-induced cardiomyopathy and improve prognosis in patients receiving chemotherapy.
Highlights
Doxorubicin (DOX) has been a widely used chemotherapy drug since the 1960s, but its widespread use is limited given its dose-dependent cardiotoxicity (Singal and Iliskovic, 1998)
One week after the last injection, increased left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) and decreased left ventricular end-diastolic diameter (LVEDD) and left ventricular end-systolic diameter (LVESD) were observed in the miR-22cKO+DOX group compared to the DOX group, which revealed that knocking out miR-22 alleviated DOXIC cardiac dysfunction (Figures 1A–E)
Masson staining suggested an increased fibrotic area in the DOX group compared to the control group, whereas knockout of miR-22 significantly alleviated fibrosis as evidenced by a smaller fibrotic area in the miR-22cKO+DOX group compared with the DOX group (Figures 1F,G)
Summary
Doxorubicin (DOX) has been a widely used chemotherapy drug since the 1960s, but its widespread use is limited given its dose-dependent cardiotoxicity (Singal and Iliskovic, 1998). Congestive heart failure (CHF) occurred in 5% of patients who received DOX treatment at a dose of 500–550 mg/m2. The incidences of CHF in DOX-treated patients at doses of 551–600 and >601 mg/m2 were 16 and 26%, respectively (Swain et al, 2003). Numerous studies have reported that DOX exerts its antineoplastic effect mainly by targeting topoisomerase-II (Top2), damaging DNA (Lyu et al, 2007), and inducing oxidative stress (Zhang et al, 2020), autophagy (Li et al, 2016), and mitochondrial dysfunction (Yin et al, 2018). It is urgent and vital to identify the underlying mechanism of DOX-induced cardiotoxicity and resolve this question.
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