Interleukin-9 Aggravates Isoproterenol-Induced Heart Failure by Activating Signal Transducer and Activator of Transcription 3 Signalling

Abstract

BackgroundPrevious studies have demonstrated that inflammation is closely related to the occurrence and development of heart failure (HF). As an inflammation-related cytokine, interleukin (IL)-9 has been reported to be involved in the development of cardiovascular diseases. However, the role of IL-9 in HF in response to isoproterenol (ISO) stimulation has barely been explored. Thus, this study aimed to investigate whether IL-9 participates in HF and the possible associated mechanisms. MethodsChronic ISO infusion was used to establish an HF model, and the IL-9 levels in mice and isolated cardiomyocytes were measured. In addition, ISO-treated mice received an injection of recombinant mouse IL-9 (rIL-9) or an antimouse IL-9 neutralizing monoclonal antibody (mAb) to investigate the effects of IL-9 on cardiac function, hypertrophy, and fibrosis. ResultsIL-9 levels were significantly increased in mice and isolated cardiomyocytes after ISO treatment. Treatment with rIL-9 resulted in aggravated cardiac dysfunction and amplified cardiac hypertrophy and fibrosis, whereas treatment with the anti-IL-9 neutralizing mAb ameliorated cardiac dysfunction and reduced cardiac hypertrophy and fibrosis in ISO-treated mice. In addition, ISO infusion–induced cardiac inflammation and cardiomyocyte apoptosis was aggravated by rIL-9 but prevented by the anti-IL-9 mAb. IL-9 did not activate signal transducer and activator of transcription (STAT)1 or STAT5 but induced STAT3 phosphorylation in ISO-induced HF. Moreover, S31-201, a specific STAT3 inhibitor, nearly abolished rIL-9-induced increases in cardiac dysfunction, hypertrophy, and fibrosis in response to ISO stimulation. ConclusionsIL-9 aggravated cardiac dysfunction and amplified cardiac hypertrophy and fibrosis in the ISO-induced HF model by activating STAT3 signalling. These data indicate that blocking IL-9 may be an attractive pharmacotherapeutic strategy for the treatment of cardiac hypertrophy and fibrosis induced by chronic β-adrenergic receptor activation to limit the progression of HF.