Aims: The 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 methods: We 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 findings: Cardiac 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.
Significance: In conclusion, CTRP1 protected against Dox-induced cardiotoxicity via activation of AKT. CTRP1 has the therapeutic potential to treat Dox-induced cardiotoxicity.
Keywords: AKT; Apoptosis; C1qTNF-related protein 1; Cardiotoxicity; Doxorubicin.
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