Introduction <p>Heart failure with preserved ejection fraction (HFpEF) is a multifactorial cardiovascular disorder characterized by diastolic dysfunction and often associated with hypertension and metabolic disturbances. We aimed to determine the inter-relationship between C/EBP homologous protein (CHOP) in b-cells and HFpEF development.</p> Methods <p>Eight-week-old male mice b-cell^flox/flox and b-cell^CHOP−/− were randomly divided into four groups: control b-cell^flox/flox and b-cell^CHOP−/− mice subjected to standard diet and water. b -cell^flox/flox and b-cell^CHOP−/− mice fed a high-fat diet (HFD) and L-NAME (0.5&#xa0;g/L) for five weeks. A comprehensive cardiovascular, metabolic, and histological evaluation was conducted.</p> Results <p>Following five weeks of HFD and L-NAME, b-cell^flox/flox mice exhibited clinical and molecular manifestations of HFpEF. These include diastolic dysfunction, a normal cardiac ejection fraction, hypertension, metabolic disorders, cardiac hypertrophy with fibrosis, pulmonary edema, renal injury, and reduced exercise tolerance. Vascular endothelial dysfunction was also observed. Western blot analysis showed a reduced phosphorylated endothelial nitric oxide synthase in mesenteric resistance arteries (MRA), concomitant with qRT-PCR data revealing elevated inflammatory and unfolded protein response markers in MRA, heart, and pancreas. Interestingly, b-cell^CHOP−/− mice subjected to an HFD and L-NAME were protected from HFpEF and its associated pathologies. These mice displayed improved cardiac and vascular endothelial function, exercise tolerance, and reduced unfolded protein response and inflammatory factors compared to their b-cell^flox/flox.</p> Conclusion <p>Our research indicates that deleting the unfolded protein response CHOP in b-cells has a robust cardiovascular protective effect against HFpEF pathogenesis. Therefore, targeting CHOP in b-cells is a promising lead for HFpEF pathogenesis therapy.</p> Graphical abstract <p></p>