Pleiotropic role of CCR9/CCL25 signaling in adriamycin-induced cardiomyopathy

Abstract

IntroductionAdriamycin (ADR)-induced cardiomyopathy is a common problem in many cancer survivors. Recently, specific chemokine receptors have garnered interest as therapeutic targets in cardiovascular diseases. ObjectivesThis study aim to report the role of C–C chemokine receptor 9 (CCR9)/C–C chemokine ligand 25 (CCL25) and its therapeutic potential in ADR-induced cardiomyopathy. MethodsFunctional gene knockout and overexpression mouse models were utilized to investigate the role of CCR9 against ADR-induced cardiomyopathy. Transcriptome sequencing was also performed to identify the downstream molecular mechanisms of CCR9. ResultsThis study revealed that CCR9 and CCL25 levels were increased in mice and HL-1 cells injured by ADR, consistent with the results of patients with heart failure. Both in vivo and in vitro, CCR9 overexpression overtly aggravated cardiac dysfunction, accompanied by decreased AMPK activity and increased mitochondrial dysfunction, fibrosis, oxidative stress, and apoptosis. However, the cardiac harmful effects of ADR were reserved by CCR9 knockdown, as well as CCR9 overexpression aggravated cardiotoxicity were reserved by AMPK agonist GSK621. By constructing different domain-missing CCR9 mutants, we suspected that the △4 region of CCR9 is important for AMPK activity. Furthermore, transcriptome sequencing further illustrated the mechanism of CCR9 overexpression aggravated ADR-induced cardiotoxicity, which was associated with CYP1A1. Finally, lithospermic acid (LA) was screened and alleviated ADR-induced cardiotoxicity through regulation of CCR9/CCL25-AMPK signaling, bolstering CCR9-targeted potential clinical application. ConclusionThese findings present a promising target and drug for treating chemotherapy-induced cardiotoxicity.