C1qTNF-related protein 1 attenuates doxorubicin-induced cardiac injury via activation of AKT

Abstract

AimsThe clinical use of doxorubicin (Dox) is limited due to a degenerative irreversible cardiac toxicity, but the precise mechanisms that contribute to this pathological response are not understood. C1q/TNF-related protein 1 (CTRP1), which is a conserved protein of the C1q family, has notable metabolic and cardiovascular functions. However, whether CTRP1 can attenuate Dox-induced cardiac injury remains unclear. Our study aimed to investigate the effect of CTRP1 on Dox-induced cardiotoxicity and assessed the mechanisms of this effect. Materials and methodsWe manipulated CTRP1 expression in the heart using in vivo gene delivery system. Two weeks after gene delivery, the mice received a single intraperitoneal injection of Dox (20 mg/kg) to induce cardiac injury. Key findingsCardiac CTRP1 protein levels were decreased in DOX-treated mice. CTRP1 overexpression reduced plasma cardiac troponin I, restored cardiac function and attenuated cardiomyocyte apoptosis in Dox-treated mice. CTRP1 also improved cell viability and reduced lactate dehydrogenase release in vitro. Dox resulted in the decreased the protein kinase B (PKB/AKT) phosphorylation, which were restored by CTRP1 overexpression. AKT inhibition offset the inhibitory effects of CTRP1 on myocyte apoptosis in vitro. CTRP1 lost its protection against Dox-induced cardiac injury in mice with AKT deficiency. Furthermore, infusion of recombinant CTRP1 protein could reverse pre-established injury in heart induced by Dox treatment. SignificanceIn conclusion, CTRP1 protected against Dox-induced cardiotoxicity via activation of AKT. CTRP1 has the therapeutic potential to treat Dox-induced cardiotoxicity.