FNDC5 alleviates oxidative stress and cardiomyocyte apoptosis in doxorubicin-induced cardiotoxicity via activating AKT

Abstract

Oxidative stress and cardiomyocyte apoptosis play critical roles in doxorubicin (DOX)-induced cardiotoxicity. Previous studies indicated that fibronectin type III domain-containing 5 (FNDC5) and its cleaved form, irisin, could preserve mitochondrial function and attenuate oxidative damage as well as cell apoptosis, however, its role in DOX-induced cardiotoxicity remains unknown. Our present study aimed to investigate the role and underlying mechanism of FNDC5 on oxidative stress and cardiomyocyte apoptosis in DOX-induced cardiotoxicity. Cardiomyocyte-specific FNDC5 overexpression was achieved using an adeno-associated virus system, and then the mice were exposed to a single intraperitoneal injection of DOX (15 mg/kg) to generate DOX-induced cardiotoxicity. Herein, we found that FNDC5 expression was downregulated in DOX-treated murine hearts and cardiomyocytes. Fndc5 deficiency resulted in increased oxidative damage and apoptosis in H9C2 cells under basal conditions, imitating the phenotype of DOX-induced cardiomyopathy in vitro, conversely, FNDC5 overexpression or irisin treatment alleviated DOX-induced oxidative stress and cardiomyocyte apoptosis in vivo and in vitro. Mechanistically, we identified that FNDC5/Irisin activated AKT/mTOR signaling and decreased DOX-induced cardiomyocyte apoptosis, and moreover, we provided direct evidence that the anti-oxidant effect of FNDC5/Irisin was mediated by the AKT/GSK3β/FYN/Nrf2 axis in an mTOR-independent manner. And we also demonstrated that heat shock protein 20 was responsible for the activation of AKT caused by FNDC5/Irisin. In line with the data in acute model, we also found that FNDC5/Irisin exerted beneficial effects in chronic model of DOX-induced cardiotoxicity (5 mg/kg, i.p., once a week for three times, the total cumulative dose is 15 mg/kg) in mice. Based on these findings, we supposed that FNDC5/Irisin was a potential therapeutic agent against DOX-induced cardiotoxicity.

The Long Noncoding RNA Hotair Regulates Oxidative Stress and Cardiac Myocyte Apoptosis during Ischemia-Reperfusion Injury

“…85-23, revised 1996), which were also approved by the Animal Care and Use Committee of the Union Hospital of Huazhong University of Science and Technology. Cardiac-restricted knockdown or overexpression of Hotair was achieved by the adeno-associated virus 9 (AAV9) system as previously described [29,30]. Briefly, mice were injected with AAV9 carrying Hotair (AAV9-Hotair, Hotair) or short hairpin RNA against Hotair (AAV9-shHotair, shHotair) under the cTnT promoter via the tail vein at a dose of 1 × 10 11 viral genome particles per mice 4 weeks before I/R surgery to overexpress or knock down Hotair in the myocardium, respectively, whereas the mice assigned to the control group were injected with AAV9-Ctrl (Ctrl) or AAV9-shCtrl (shCtrl).…”

FNDC5/Irisin improves the therapeutic efficacy of bone marrow-derived mesenchymal stem cells for myocardial infarction

“…Third-passage BM-MSCs with optimal growth at the third generation were applied for different treatments to avoid contamination with other types cell. Then, cells were treated with irisin (20 nmol/L) in the presence or absence of hypoxia for 48 h (19) .…”

“…Furthermore, irisin has been considered as a multifunctional peptide which is involved in regulating cardiovascular function (13,17,18) . Meanwhile, accumulating studies demonstrated that irisin was involved in cardioprotective effect, such as anti-apoptosis, increased cells viability and anti-oxidative stress by various pathways (19)(20) .…”

Calycosin ameliorates doxorubicin‐induced cardiotoxicity by suppressing oxidative stress and inflammation via the sirtuin 1–NOD‐like receptor protein 3 pathway

“…Forty mice were divided into four groups: control, DOX, DOX + CA (50 mg/ kg), and DOX + CA (100 mg/ kg), by a random number table. The DOX + CA (50 mg/ kg) and DOX + CA (100 mg/ kg) mice were injected with 50 or 100 mg/ kg of CA intraperitoneally once daily for 7 days and administration of a single intraperitoneal injection of DOX (15 mg/ kg) to induce short-term model for cardiomyopathy on the fifth day (Zhang & Hu, 2019). Mice in the control group received saline injections only.…”