Novel insights into beta cell ER stress CHOP and its role in HFpEF development

Document Type

Article

Publication Date

6-13-2025

Publication Title

Cardiovascular diabetology

Abstract

INTRODUCTION: 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.

METHODS: 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 g/L) for five weeks. A comprehensive cardiovascular, metabolic, and histological evaluation was conducted.

RESULTS: 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).

CONCLUSION: 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.

Medical Subject Headings

Animals; Transcription Factor CHOP; Male; Disease Models, Animal; Heart Failure; Endoplasmic Reticulum Stress; Stroke Volume; Mice, Knockout; Ventricular Function, Left; Insulin-Secreting Cells; Mice, Inbred C57BL; Signal Transduction; Diet, High-Fat; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase Type III; Mice

PubMed ID

40514660

Volume

24

Issue

1

First Page

250

Last Page

250

Find It @ Sladen

Share

COinS