Inhibition of miR-128-3p Attenuated Doxorubicin-Triggered Acute Cardiac Injury in Mice by the Regulation of PPAR-γ

Abstract

Background. The clinical usefulness of doxorubicin (DOX), an anthracycline with antitumor activity, is limited by its cardiotoxicity. Oxidative stress and myocardial apoptosis were closely associated with DOX-induced cardiac dysfunction. It has been reported that microRNA-128-3p (miR-128-3p) was involved into the regulation of redox balance. However, the role of miR-128-3p in DOX-related cardiac injury remains not yet understood. The aim of this study was to investigate the biological effect of miR-128-3p in DOX-induced cardiotoxicity. Methods. To induce DOX-related acute cardiac injury, mice were subjected to a single injection of DOX. Inhibition of myocardial miR-128-3p was achieved by an adeno-associated virus (AAV9) system carrying a miR-128-3p sponge. Results. The data in our study indicated that miR-128-3p was upregulated in DOX-treated hearts and cardiomyocytes. Inhibition of miR-128-3p attenuated DOX-related cardiac injury and improved cardiac function in mice. Moreover, miR-128-3p inhibition could suppress myocardial inflammatory response, oxidative damage, and cell apoptotic death in DOX-treated mice. Further analysis showed that miR-128-3p could directly target peroxisome proliferator-activated receptor γ (PPAR-γ) and decrease PPAR-γ expression. Moreover, the protective effects provided by miR-128-3p inhibition were abolished by a PPAR-γ antagonist in vivo and in vitro. Conclusions. miR-128-3p inhibition attenuated DOX-related acute cardiac injury via the regulation of PPAR-γ in mice.

Cardiomyocyte Atrophy, an Underestimated Contributor in Doxorubicin-Induced Cardiotoxicity

“…Little doxorubicin-induced apoptotic effect in acute DIC model was reported by other groups (41)(42)(43)(44). However, it was also reported that DOX caused a great amount of apoptotic cardiomyocyte in an acute DIC model (45)(46)(47). Maybe apoptosis plays less important role in cardiac atrophy of acute DIC than we thought.…”

MicroRNA-1224-5p Aggravates Sepsis-Related Acute Lung Injury in Mice

“…To inhibit AMPK α , mice were intraperitoneally with CpC (20 mg/kg) once two days for 3 times before miR-1224-5p antagomir treatment [ 4 ]. To inhibit PPAR- γ , mice were pretreated with GW9662 (0.35 mg/kg/day in drinking water) for 10 consecutive days as previously described [ 27 , 28 ]. The animal protocols were approved by the Animal Experimentation Ethics Committee of Zhongnan Hospital of Wuhan University and were also in accordance with the guidelines of the National Institutes of Health for live animals.…”

“…To investigate the role of miR-1224-5p in vitro , cells were pretreated with the miR-1224-5p agomir (50 nmol/L), antagomir (50 nmol/L), or corresponding controls using Lipo6000™ Transfection Reagent for 24 h, cultured in fresh medium for an additional 24 h, and then stimulated with or without LPS (100 ng/mL) for 6 h [ 4 , 19 ]. To inhibit AMPK α or PPAR- γ , cells were preincubated with CpC (20 μ mol/L) or GW9662 (10 μ mol/L) for 12 h before miR-1224-5p antagomir treatment [ 4 , 27 ].…”

MicroRNAs in doxorubicin-induced cardiotoxicity: The DNA damage response

“…Upon binding, the complex associates with the miR-128 promoter region, increasing miR-128 expression (Li et al, 2015). An increased miR-128 level was reported in DOX-treated hearts (Zhang et al, 2021b). miR-128 promotes apoptosis by inhibiting SIRT1, resulting in increased p53 acetylation and activity (Adlakha and Saini, 2013;Li et al, 2015).…”