Abstract
Ulcerative colitis and Crohn’s disease are classified as chronic inflammatory bowel diseases (IBD) with known extraintestinal manifestations. The interplay between heart and gut in IBD has previously been noted, but the mechanisms remain elusive. Our objective was to identify microRNAs mediating molecular remodeling and resulting cardiac impairment in a rat model of colitis. To induce chronic colitis, dextran sodium sulfate (DSS) was given to adult rats for 5 days followed by 9 days with normal drinking water for 4 cycles over 8 weeks. Echocardiography was performed to evaluate heart function. DSS-induced colitis led to a significant decrease in ejection fraction, increased left ventricular mass and size, and elevated B-type natriuretic protein. MicroRNA profiling showed a total of 56 miRNAs significantly increased in the heart by colitis, 8 of which are predicted to target brain-derived neurotrophic factor (BDNF). RT-qPCR validated the increases of miR-1b, Let-7d, and miR-155. Transient transfection revealed that miR-155 significantly suppresses BDNF in H9c2 cells. Importantly, DSS colitis markedly decreased BDNF in both myocardium and serum. Levels of various proteins critical to cardiac homeostasis were also altered. Functional studies showed that BDNF increases cell viability and mitigates H2O2-induced oxidative damage in H9c2 cells, demonstrating its protective role in the adult heart. Mechanistically, cellular experiments identified IL-1β as the inflammatory mediator upregulating cardiac miR-155; this effect was confirmed in adult rats. Furthermore, IL-1β neutralizing antibody ameliorated the DSS-induced increase in miR-155 and concurrent decrease in BDNF in the adult heart, showing therapeutic potential. Our findings indicate that chronic colitis impairs heart function through an IL-1β→miR-155→BDNF signaling axis.
Highlights
Inflammatory bowel disease (IBD) represents a spectrum of chronic inflammatory mediated conditions, including Crohn’s disease and ulcerative colitis, manifesting in varying degrees and locations of colitis
These physiologic changes noted in chronic colitis were accompanied by an increase in serum levels of B-type natriuretic peptide (BNP) (2.4-fold, Fig 1J), a biochemical marker for heart failure, which is strongly associated with LV hypertrophy [30]
Population-based studies found that IBD is associated with increased risk of hospitalization for heart failure [3,40], developing ischemic stroke [41], and myocardial infarction [17,42]
Summary
Inflammatory bowel disease (IBD) represents a spectrum of chronic inflammatory mediated conditions, including Crohn’s disease and ulcerative colitis, manifesting in varying degrees and locations of colitis. While therapeutic research has been primarily targeted on affecting the pathways yielding abnormal colonic inflammation, IBD has known extraintestinal manifestations mediated through a chronic inflammatory and hypercoagulable state [1]. Chronic inflammation has previously been identified as atherogenic with increased risk of developing cardiovascular disease. Patients with IBD diagnosed for greater than a year were noted to have an increased incidence of coronary artery disease events compared to controls despite having fewer risk factors for coronary artery disease [4]. Crohn’s disease and ulcerative colitis have been identified as independent risk factors for acute myocardial infarction [5]. Despite the independent recognition of IBD as a risk factor for heart disease, the mechanisms mediating the changes in cardiac function in patients with IBD have not been well elucidated, partly due to unavailability of human heart tissue
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