A new mechanism of right ventricular remodeling by Interleukin-22 under right ventricular pressure overload

Abstract Background Fibrosis and remodeling of the right ventricle (RV) are associated with prognosis in patients with RV failure. Interleukin-22 (IL-22) is a member of the IL-10 cytokine family, which plays roles in tissue protection and wound repair. We have previously shown that IL-22 has an important role in cardiac remodeling after acute myocardial infarction; however, the role of IL-22 in RV fibrosis and remodeling remains elusive. Purpose We investigated the role of IL-22 in the pathogenesis of RV remodeling during pressure overload. Methods Pulmonary artery banding (PAB) was performed by placing a 6-0 suture around the pulmonary artery over a 24 G needle in wild-type mice (C57BL/6J) and IL-22 knockout mice (IL-22 KO). Only mice with moderate pulmonary artery stenosis (peak pressure gradient across the pulmonary band 25 mmHg at 1 week after surgery, as measured by Doppler echocardiography) were included in the study. Four weeks after PAB, RV function was measured by echocardiography and histomorphology. Transcriptome analysis was performed on mRNA samples isolated from the RV, and differentially expressed genes were identified by EdgeR (p 0.05). Additionally, the survival of mice with moderate pulmonary artery stenosis was monitored for up to 56 days. Results IL-22 KO mice had a significantly higher 56-day mortality rate compared to WT mice after PAB (p0.01). IL-22 KO mice exhibited significant RV enlargement and dysfunction 4 weeks after PAB (RVEDV: 10±2.3mm2 vs 12.9±3.1mm2, p 0.01; FAC: 35.2±7.8% vs 23±6.0%, p 0.01). Four weeks after PAB, the frequency of tricuspid regurgitation (TR) was significantly higher in IL-22 KO mice than in wild-type mice (100% vs 30%, p 0.01). Transcriptome analysis revealed that genes associated with extracellular matrix (ECM) organization, including collagen formation - such as Col3a1 and Col5a2, which contribute to fibrosis during RV failure - were less upregulated in IL-22 KO mice after PAB, despite echocardiographic findings indicating reduced RV function. Notably, genes related to elastic fiber formation, such as Fbn1, Loxl1 and Eln, were also significantly less elevated in IL-22 KO mice compared to WT mice after PAB. Consistent with the results of the transcriptome analysis, histological assessment showed that fibrotic and elastic fiber areas were significantly smaller in IL22-KO mice at 4 weeks after PAC, as determined by Picro-Sirius red staining and resorcin-fuchsin staining. (Fibrotic area: 31.2±5.8% vs 21.2±9.1%, p = 0.01; elastic fiber area: 11.5±4.1% vs 6.9±3.7%, p = 0.46). Conclusions These results suggest that IL-22 may play a unique mechanistically prophylactic role in RV remodeling and TR development during pressure overload by contributing to structural integrity and the regulation of adaptive fibrosis.