P4758Experimental colitis impedes cardiac function through epigenetic mechanisms

Abstract

Background: Inflammatory bowel disease (IBD) is an idiopathic and immunologically mediated condition, causing gastrointestinal symptoms such as diarrhoea, passage of blood, abdominal pain, and weight loss. The incidence of IBD is increasing worldwide. IBD patients often develop various complications, including increased risk of heart failure, ischaemic stroke, and thromboembolic events. However, the molecular mechanisms by which IBD predisposes some patients to cardiovascular diseases remain elusive. Purpose: This project aims to identify epigenetic mechanisms by which experimental colitis epigenetically remodels adult heart to impair cardiac function. Methods: To induce colonic inflammation in adult rats, we administered dextran sodium sulfate (DSS, 3% in drinking water) for 3 cycles of 7 days each, with intermittent 2-week intervals of normal drinking water. Seven days after the last cycle of DSS, echocardiography was performed to evaluate cardiac function and all animals were euthanised for tissue collection. Results: Ultrasound revealed that left ventricular ejection fraction (LVEF) was significantly reduced after 3 cycles of DSS (77.9% vs 65.7%, P<0.01), whereas LV mass was markedly increased (107.1 vs 147.8, P<0.05). Serum B-type natriuretic peptide (BNP) was significantly upregulated by DSS (487 vs 221 pg/ml, P<0.05), suggesting that colitis impedes heart function. To assess epigenetic remodelling, total RNA was extracted from individual heart and miRNA arrays were performed. We found that 30 miRNAs, including miR-423-5p, a potential biomarker for heart failure, were significantly elevated, whereas 38 miRNAs were significantly downregulated. Real-time PCR analyses confirmed the elevation of miR-1-3p, let-7d- 3p, and miR-423-5p by DSS colitis. Since miR-1-3p targets brain-derived neurotrophic factor (BDNF), which regulates cardiac contraction force and protects against cardiac dysfunction, we evaluated BDNF levels. Serum BDNF was significantly decreased in animals receiving DSS (96.5 vs 5.7 pg/ml, P<0.05). BDNF mRNA levels were also significantly downregulated in the heart by DSS colitis (P<0.05), suggesting that epigenetic downregulation of BDNF may contribute to cardiac impairment. To determine the role of BDNF in regulating cardiac function, we created a cardiac-specific conditional BDNF knockout mouse line. Cardiac function and disease susceptibility to DSS are being evaluated. We also carried out an intervention study with aspirin in this DSS rat model. Supplementation of aspirin in drinking water (0.01%) ameliorated the decreases of LVEF and serum BDNF as well as the increases of LV mass, miR-1-3p, and serum BNP in DSStreated animals. Conclusions: Chronic colitis causes epigenetic remodelling, including marked changes in miRNA expression profiles, in adult heart. We are now pursuing the in-depth mechanisms by which epigenetic modifications contribute to cardiac impairment, via the repression of BDNF.