Cardiomyocyte-Restricted Expression of IL11 Causes Cardiac Fibrosis, Inflammation, and Dysfunction.

Cardiac fibrosis is a common pathological process in heart disease, representing a therapeutic target. Transforming growth factor ß (TGFß) is the canonical driver of cardiac fibrosis and was recently shown to be dependent on interleukin 11 (IL11) for its profibrotic effects in fibroblasts. In the opposite direction, recombinant human IL11 has been reported as anti-fibrotic and anti-inflammatory in the mouse heart. In this study, we determined the effects of IL11 expression in cardiomyocytes on cardiac pathobiology and function. We used the Cre-loxP system to generate a tamoxifen-inducible mouse with cardiomyocyte-restricted murine Il11 expression. Using protein assays, bulk RNA-sequencing, and in vivo imaging, we analyzed the effects of IL11 on myocardial fibrosis, inflammation, and cardiac function, challenging previous reports suggesting the cardioprotective potential of IL11. TGFß stimulation of cardiomyocytes caused Il11 upregulation. Compared to wild-type controls, Il11-expressing hearts demonstrated severe cardiac fibrosis and inflammation that was associated with the upregulation of cytokines, chemokines, complement factors, and increased inflammatory cells. IL11 expression also activated a program of endothelial-to-mesenchymal transition and resulted in left ventricular dysfunction. Our data define species-matched IL11 as strongly profibrotic and proinflammatory when secreted from cardiomyocytes and further establish IL11 as a disease factor.

Imprinted Genes Impact Upon Beta Cell Function in the Current (and Potentially Next) Generation.

Beta cell failure lies at the centre of the aetiology and pathogenesis of type 2 diabetes and the epigenetic control of the expression of critical beta cell genes appears to play a major role in this decline. One such group of epigenetically-controlled genes, termed 'imprinted' genes, are characterised by transgenerational monoallelic expression due to differential allelic DNA methylation and play key functional roles within beta cells. Here, we review the evidence for this functional importance of imprinted genes in beta cells as well as their nutritional regulation by the diet and their altered methylation and/or expression in rodent models of diabetes and in type 2 diabetic islets. We also discuss imprinted genes in the context of the next generation, where dietary overnutrition in the parents can lead to their deregulation in the offspring, alongside beta cell dysfunction and defective glucose handling. Both the modulation of imprinted gene expression and the likelihood of developing type 2 diabetes in adulthood are susceptible to the impact of nutritional status in early life. Imprinted loci, therefore, represent an excellent opportunity with which to assess epigenomic changes in beta cells due to the diet in both the current and next generation.