CTRP3 Influenced Doxorubicin-induced Cardiotoxicity

Background:Doxorubicin(DOX)is one of the most effective chemotherapeutic drugs for the treatment of cancer.However,the inflammation and myocytes apoptosis play critical roles in the development of doxorubicin(DOX)-induced cardiotoxicity,limiting the application of DOX.DOX has been proved to increase pro-inflammation factors,activate the nuclear factor-κB(NF-κB)pathway and lead to cardiotoxicity ultimately.Clq/tumour necrosis factor-related protein-3(CTRP3)is a newly discovered adipokine and has been identified as a member of highly conserved CTRP superfamily of adipose tissue-derived cytokines.Our previous study found that CTRP3 could inhibit cardiac inflammation and apoptosis of myocytes but its role in DOX-induced heart injury remains largely unknown.Our study aimed to investigate whether CTRP3 protected against DOX-induced heart injury and the underlying mechanism.Methods:We overexpressed CTRP3 in the hearts using an adeno-associated virus system.The mice were subjected to a single intraperitoneal injection of DOX 15mg/kg or 5mg/kg/w to induce acute or chronic model for cardiomyopathy.Echocardiography and hemodynamics were used to assessed the cardiac function of mice from different groups.After that,mice were weighted,recorded and hearts were dissected for further pathological examination and molecular biological detection.The expression of pro-inflammation factors and apoptosis factors were measured by Western blot.The total RNA of cardiac were extracted and tested the mRNA level of tumor necrosis factor-α(TNF-α),Interleukin-1β(IL-1β),Interleukin-6(IL-6)and monocyte chemotactic protein-1(MCP-1)and several apoptosis related factors.HE staining,immunohistochemistry,immunofluorescence and so on were used to evaluate the effects of CTRP3.Moreover,we cultured H9C2 cells and extracted protein and RNA and repeated all the ditections to verify the protective role of CTRP3 in vitro.Results:Myocardial CTRP3 protein levels were reduced in DOX-treated mice.Cardiac specific-overexpression of CTRP3 preserved the decrease of body weight,shortening fraction and maximal rate of pressure development(dp/dt max)induced by DOX.Meanwhile,CTRP3 also attenuated the expression level of inflammation factors,like TNF-α,and the nuclear translocation of NF-κB.Compared with DOX group,the level of TUNEL positive cells decreased in DOX+CTRP3 group.In chronic model,CTRP3 also attenuated the decrease of HW/TL,FS and +dP/dt,the increase of BNP,the nuclear translocation of NF-κB and the increase of TUNEL positive cells.Moreover,the silence of Sirtl abolish the effects of CTRP3 against DOX-induced inflammation and apoptosis.Similarly,EX-527 also blocked the effects of CTRP3 in DOX-induced inflammation and apoptosis.Conclusion:CTRP3 protected against DOX-induced heart injury via activation of Sirtl.CTRP3 has therapeutic potential for the treatment of DOX cardiotoxicity.