Abstract 4141025: Interleukin-22 Prevents Right Ventricular Remodeling and Tricuspid Regurgitation during Pressure Overload through a Unique Mechanism

Introduction: Right ventricle (RV) remodeling is associated with prognosis in patients with RV failure. Interleukin-22 (IL-22) is a member of the IL-10 cytokine family, play roles in tissue protection and wound repair. We have previously shown that IL-22 plays an important role in left ventricular remodeling after acute myocardial infarction; however, the role of IL-22 in the development of RV remodeling remains elusive. Hypothesis: IL-22 would inhibit the development of RV remodeling during pressure overload. Methods: Pulmonary artery banding (PAB) is 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 by echo Doppler) were included in the study protocol. Four weeks after PAB, RV function was measured by echocardiography and transcriptome analysis was performed on mRNA samples isolated from the RV and differentially expressed genes were identified by EdgeR (p<0.05). Survival confirmation of mice with moderate pulmonary artery stenosis was also performed up to 56 days. Results: IL-22 KO mice had significantly higher 56-day mortality rate compared with WT mice after PAC (p<0.01). Four weeks after PAB, IL-22 KO mice showed markedly increased RV weight (IL-22 KO mice vs. wild-type mice; RV/LV+IVS: 0.48±0.05 vs 0.40±0.02, P=0.002). IL-22 KO mice exhibited significant RV enlargement and RV dysfunction 4 weeks after PAB. (RVEDV: 10±2.3mm2 vs 12.9±3.1mm2, P=0.005, FAC: 35.2±7.8% vs 23±6.0%, P<0.001). Four weeks after PAB, the frequency of tricuspid regurgitation (TR) in IL-22 KO mice was significantly higher than that in wild type mice (100% vs 30%, P=0.004).Transcriptome analysis showed that genes related to extracellular matrix (ECM) organization, including collagen formation, which are involved in fibrosis during RV failure, were less upregulated in Il-22 KO mice after PAB, in contrast to the echo results of reduced RV function. Interestingly, genes related to elastic fiber formation, such as Fbn1 and Eln, were particularly less elevated in Il-22 KO mice compared to WT mice after PAB. Conclusions: These results suggest that IL-22 may play a prophylactic role in RV remodeling and tricuspid regurgitation development during pressure overload through a unique mechanism.