Chronic Colitis Impairs Heart Function by Inducing Epigenetic Remodeling in the Adult Heart

Abstract

Abstract Background and Aims Inflammatory bowel disease (IBD) represents a spectrum of chronic inflammatory mediated conditions with known extraintestinal manifestations. The interplay between heart and gut in IBD has previously been noted, but the mechanisms remain elusive. The aim of this study was to identify epigenetic mechanisms by which chronic colitis impairs cardiac function. Methods To induce chronic colitis, dextran sodium sulfate (DSS, 5% in drinking water) was given to adult rats for 5 days followed by 9 days with normal drinking water for 4 cycles over 8 weeks. Transthoracic echocardiography (TTE) was performed to evaluate heart function. Results DSS-induced chronic colitis led to a significant decrease in left ventricular ejection fraction on TTE (68% vs 49%, P<0.05), increased left ventricular mass (107 vs 148, P<0.05), and increased B-type natriuretic protein (222 vs 487, P<0.05). Cardiac and circulating BDNF, as well as GSK-3β, BCL2 and pAKT(S133), was markedly decreased. BDNF was also decreased in colitis induced by trinitrobenzene sulfonic acid. MiRNA profiling showed a total of 52 miRNAs significantly increased in DSS colitis, 7 of which are predicted to target BDNF. RT-qPCR subsequently validated the increase of miR-1b, Let-7d, and miR-155-5p in the adult heart by colitis. Transient transfection demonstrated that miR-1b, Let-7d, and miR-155-5p suppress BDNF in H9c2 rat myoblasts. BDNF overexpression mitigated H2O2-induced oxidative damage n H9c2 cells. Cardiac-specific conditional knockout of BDNF enlarged the heart size and impaired cardiac function. Conclusions Chronic colitis suppresses cardiac BDNF by elevating miRNAs; this was accompanied by biochemical and TTE findings suggestive of heart failure.