People with diabetes have a two to five time higher risk of developing cardiovascular diseases. For decades physicians have noticed unhealthy changes in the hearts of diabetics called diabetic cardiomyopathy, which is a disorder of the heart muscle that can lead to heart failure. However, the molecular mechanisms responsible for this cardiac disorder are poorly understood, although they are key to revealing new targets for the discovery of better treatments and development of more accurate diagnostics. Now, a study from researchers led by The University of Texas Medical Branch at Galveston has identified a molecular mechanism involved in a common form of heart damage found in people with diabetes. The team state their findings show that RBFOX2 being dysregulated by a dominant-negative isoform of RBFOX2 (DN RBFOX2) is an early pathogenic event in diabetic hearts. The opensource study is published in the journal Cell Reports.
Previous studies show that RNA provides the blueprint for making the protein building blocks of cells. RNA is cut or spliced to generate mRNA used to build proteins. RNA splicing mistakes are associated with many human diseases because they lead to production of harmful proteins. Earlier studies from the lab have shown that splicing is incorrectly regulated with levels of the splicing regulator RBFOX2 elevated in diabetic heart tissue. The current study investigates how RBFOX2 regulation contributes to splicing defects seen in diabetic hearts and how this effects cardiac function.
The current study shows that RBFOX2 binds to 73% of the RNA that are mis-spliced in diabetic heart tissues. Results show that this alternative splicing impairs normal gene expression patterns in the heart, especially genes important for molecular metabolism, programmed cell death, protein trafficking and calcium handling in heart muscle tissue.
Results show that the RNA-binding protein RBFOX2 contributes to transcriptome changes under diabetic conditions; RBFOX2 controls alternative-splicing of genes with important roles in heart function relevant to diabetic cardiomyopathy. Data findings show that RBFOX2 protein levels are elevated in diabetic hearts despite low RBFOX2 alternative-splicing activity. The group observed that a DN isoform of RBFOX2 that blocks RBFOX2-mediated alternative-splicing is generated in diabetic hearts. They go on to note that DN RBFOX2 expression is specific to diabetes and occurs at early stages before cardiomyopathy symptoms appear.
The team surmise that their findings show that RBFOX2 function is disrupted in diabetic hearts before cardiac complications are noticeable and RBFOX2 dysregulation contributes to abnormal calcium signaling in the heart. For the future, the researchers state that identifying RBFOX2 as an important contributor to diabetic complications and learning how it is dysregulated may allow the global medical community to develop new tools to diagnose, prevent or treat diabetic cardiomyopathy in the future.