CTRP5 Attenuates Doxorubicin-Induced Cardiotoxicity Via Inhibiting TLR4/NLRP3 Signaling.

Abstract

C1q/tumor necrosis factor-related protein 5 (CTRP5) has been reported to be a crucial regulator in cardiac ischemia/reperfusion (I/R) injury. Nevertheless, the potential role of CTRP5 in doxorubicin (DOX)-induced cardiotoxicity and the potential mechanisms remain largely unclear. We overexpressed CTRP5 in the hearts using an adeno-associated virus 9 (AAV9) system through tail vein injection. C57BL/6 mice were subjected to DOX (15 mg/kg/day, i.p.) to generate DOX-induced cardiotoxicity for 4 weeks. Subsequently, cardiac staining and molecular biological analysis were performed to analyze the morphological and biochemical effects of CTRP5 on the cardiac injury. H9c2 cells were used for validation in vitro. CTRP5 expression was down-regulated after DOX treatment both in vivo and in vitro. CTRP5 overexpression significantly attenuated DOX-induced cardiac injury, cardiac dysfunction, inhibited oxidative stress and inflammatory response. Mechanistically, CTRP5 overexpression markedly decreased the protein expression of toll-like receptor 4 (TLR4), NLRP3, cleaved caspase-1 and caspase-1, indicating TLR/NLRP3 signaling contributes to the cardioprotective role of CTRP5 in DOX-induced cardiotoxicity. Together, our findings demonstrated that CTRP5 overexpression could protect the heart from oxidative stress and inflammatory injury induced by DOX through inhibiting TLR4/NLRP3 signaling, suggesting that CTRP5 might be a potential therapeutic target in the prevention of DOX-induced cardiotoxicity.