ER stress CHOP Knockout in Beta Cells protects from type 2 diabetes-induced vascular dysfunction

Abstract

Introduction: Cardiovascular complications are the primary causes of morbidity and mortality in patients with type 2 diabetes (T2D). T2D is a significant risk factor for cardiovascular diseases such as coronary artery disease, stroke, peripheral vascular disease, and heart failure for millions of people in the US. In the present study, we determined the role of the endoplasmic reticulum stress (ER) stress C/EBP homologous protein (CHOP) in beta cells on type 2 diabetes-induced vascular endothelial dysfunction. Methods: male and female CHOPflox/flox and CHOPbeta cells −/− mice were fed a high-fat diet (HFD) for 12 weeks. We measured body weight, running distance, heart/lung/pancreas/kidney weights, glucose tolerance test (GTT), vascular endothelial function, and signaling. Results: Our research indicates that mice with the ER stress CHOPflox/flox genotype, when fed a high-fat diet for 12 weeks, develop obesity and show impaired GTT and running distance. Additionally, they exhibit an increase in the weight of organs such as the heart, lungs, pancreas, and kidneys and experience vascular endothelial dysfunction and a reduction in phosphorylated eNOS levels. However, it's interesting to note that mice that lack the ER stress CHOPbeta cells−/− and were fed the same high-fat diet for 12 weeks displayed a protective effect. Conclusion: The data indicates that beta cell ER stress CHOP plays an essential role in type 2 diabetes. Disrupting the ER stress CHOP, specifically in beta cells, has been shown to protect mice from the vascular endothelial dysfunction caused by type 2 diabetes. Therefore, targeting ER stress CHOP, specifically in beta cells, could be a promising therapeutic approach to safeguard vascular endothelial function. NIH-HL150014 (Matrougui) and NIH-HL151616 (Matrougui). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.