Deletion of CHOP in beta cell protects mice from cardiovascular complications in type 2 diabetes: evidence from a pre-clinical mouse model.

INTRODUCTION: Cardiovascular complications are the leading cause of morbidity and mortality in patients with type 2 diabetes (T2D), which is recognized as a major independent risk factor for coronary artery disease, stroke, peripheral vascular disease, and heart failure. The interrelationship between metabolic dysfunction and cardiovascular disease is complex and multifactorial, involving hyperglycemia, insulin resistance, inflammation, and oxidative stress. Evidence indicates that endoplasmic reticulum (ER) stress and induction of the unfolded protein response (UPR) contribute to metabolic dysregulation and vascular dysfunction. However, the specific role of beta cell-derived UPR mediators, particularly C/EBP homologous protein (CHOP), in coordinating this interorgan axis between the endocrine pancreas and the cardiovascular system remains poorly understood.

METHODS: To determine the role of beta cell CHOP in mediating the link between T2D and cardiovascular complications, we specifically deleted CHOP in beta cells. Thus, male and female β-cellflox/flox and β-cell-specific CHOP knockout (β-cellCHOP-/-) mice were fed a high-fat diet (HFD) or a control diet for four months. Metabolic, cardiovascular, and inflammatory parameters were assessed, including body weight, exercise capacity as measured by running distance, organ weights (heart, lung, pancreas, and kidney), glucose tolerance test (GTT), vascular endothelial function, cardiac fibrosis, and the expression of ER stress and inflammatory signaling markers.

RESULTS: β-cellflox/flox mice fed HFD for four months develop hallmark features of T2D, including obesity, glucose intolerance, impaired exercise capacity, cardiac fibrosis, vascular endothelial dysfunction, and increased organ weights. In contrast, β-cellCHOP-/- mice are protected from these complications, demonstrating preserved glucose tolerance, endothelial function, reduced cardiac fibrosis, enhanced exercise performance, and blunted activation of ER stress and inflammatory pathways.

CONCLUSION: This study elucidates CHOP in pancreatic beta cells as a key mechanism linking T2D to cardiovascular complications. Deleting CHOP in beta cells reduces metabolic and cardiovascular issues, underscoring the role of beta cell stress in the connection between T2D and cardiovascular disease. These findings suggest that CHOP may be a potential target for preventing T2D-related cardiovascular complications.