Key result
CCR9 overexpression aggravated adriamycin-induced cardiotoxicity via decreased AMPK activity, whereas CCR9 knockdown or lithospermic acid alleviated these harmful cardiac effects.
Why the study?
Adriamycin-induced cardiomyopathy is common in cancer survivors, and this study investigated the role and therapeutic potential of CCR9/CCL25 signaling in this condition.
CCR9/CCL25 signaling mediates adriamycin-induced cardiomyopathy via AMPK, and targeting this pathway with lithospermic acid offers a potential therapeutic strategy.
Hypothesis-generating for CCR9/CCL25-AMPK modulation in ADR cardiomyopathy; prospective human trials needed before clinical consideration.
• CCR9 and CCL25 levels were increased in myocardial tissues from ADR-injured mice or ADR-injured HL-1 cardiomyocytes. • CCR9/CCL25-mediated signaling machinery mitigated ADR-induced cardiotoxicity through multiple pathological mechanism. • AMPK serves as a cardinal molecule mediating CCR9/CCL25 signaling. • Lithospermic acid alleviated ADR-induced cardiotoxicity through regulation of CCR9/CCL25-AMPK signaling. Adriamycin (ADR)-induced cardiomyopathy is a common problem in many cancer survivors. Recently, specific chemokine receptors have garnered interest as therapeutic targets in cardiovascular diseases. This 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. Functional 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. This 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. These findings present a promising target and drug for treating chemotherapy-induced cardiotoxicity.
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Wu et al. (2024) studied Adriamycin-induced cardiomyopathy. CCR9/CCL25 signaling modulation was evaluated on Cardiac dysfunction and cardiotoxicity. CCR9 overexpression aggravated adriamycin-induced cardiotoxicity via decreased AMPK activity, whereas CCR9 knockdown or lithospermic acid alleviated these harmful cardiac effects.
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