Possible involvement of downregulation of the apelin-APJ system in doxorubicin-induced cardiotoxicity.

Abstract

Apelin peptide is an endogenous ligand of APJ (a putative receptor protein related to the angiotensin II type 1 receptor), which is a member of a G protein-coupled receptor superfamily with seven transmembrane domains. Recent findings have suggested that the apelin-APJ system plays a potential role in cardiac contraction and cardioprotection. In the present study, we show that the apelin-APJ system is disrupted in doxorubicin (Dox)-induced cardiotoxicity. We found downregulation of apelin and APJ mRNA expression in C57Bl/6J mouse hearts on days 1 and 5 after Dox administration (20 mg/kg ip). Plasma apelin levels and cardiac APJ protein expression were significantly decreased on day 5 after Dox injection. Cardiac apelin contents were reduced on day 1 but increased to basal levels on day 5 after Dox injection. We also examined the effects of APJ gene deletion on Dox-induced cardiotoxicity. Compared with wild-type mice, APJ knockout mice showed a significant depression in cardiac contractility on day 5 after Dox (15 mg/kg ip) treatment followed by a decrease in 14-day survival rates. Moreover, Dox-induced myocardial damage, cardiac protein carbonylation, and autophagic dysfunction were accelerated in APJ knockout mice. Rat cardiac H9c2 cells showed Dox-induced decreases in viability, which were prevented by APJ overexpression and the combination with apelin treatment. These results suggest that the suppression of APJ expression after Dox administration can exacerbate Dox-induced cardiotoxicity, which may be responsible for depressed protective function of the endogenous apelin-APJ system. Modulation of the apelin-APJ system may hold promise for the treatment of Dox-induced cardiotoxicity.