Combination of genetic eNOS deficiency and high-fat diet induces reproducible cardiometabolic HFpEF
6 affiliations
- 1Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- 2Vascular Metabolism Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA
- 3Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
- 4Northwestern University Medicine, Feinberg School of Medicine, Chicago, IL, USA
- 5Department of Anesthesiology & Perioperative Medicine, Medicine and Physiology, Molecular Biology Institute, David Geffen School of Medicine at University of California, Los Angeles, CA, USA
- 6Department of Cardiac Surgery, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Corresponding author. Department of Cardiac Surgery Smidt Heart Institute, Cedars-Sinai Medical Center, 127 S. San Vincente Boulevard, Los Angeles, CA. 90048, USA.
Abstract
Heart failure with preserved ejection fraction (HFpEF) is a complex, multi-organ cardiometabolic syndrome lacking universally effective therapies. We developed and validated a robust murine model leveraging complete, constitutive genetic endothelial nitric oxide synthase deficiency (eNOS KO) coupled with metabolic stress via a high-fat diet (HFD) in both male and female cohorts. eNOS KO mice subjected to HFD (10 weeks for males; 15 weeks for females) developed a severe and highly reproducible cardiometabolic HFpEF phenotype. Despite preserved left ventricular ejection fraction, both sexes exhibited profound diastolic dysfunction, characterized by elevated E/e’ ratios and left ventricular end-diastolic pressures (LVEDP), alongside severe exercise intolerance. Consistent with the systemic clinical syndrome, pathological remodeling extended to multi-organ damage, featuring prominent cardiac fibrosis, severe hepatic steatosis, and renal tubulointerstitial fibrosis. Finally, chronic administration of the dual GIP/GLP-1 receptor agonist tirzepatide largely reversed the hemodynamic, functional, and systemic fibrotic derangements. In conclusion, this novel eNOS KO mouse + HFD model provides a rapidly developing, highly penetrant, and chemically unconfounded platform that ensures robust HFpEF induction across both sexes. This model can be readily adopted for the investigation of mechanistic insights into HFpEF pathobiology and for the study of novel HFpEF therapeutics.
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BibTeX
@article{elbatreek2026combination,
title = {{Combination of genetic eNOS deficiency and high-fat diet induces reproducible cardiometabolic HFpEF}},
author = {Mahmoud H. Elbatreek and Vinayak S. Khodade and Darshan Amin and Miguel Huerta and Timothy D. Allerton and David J. Polhemus and Sanjiv J. Shah and Thomas M. Vondriska and Traci T. Goodchild and David J. Lefer},
journal = {Redox Biology},
year = {2026},
month = oct,
doi = {10.1016/j.redox.2026.104394},
url = {https://doi.org/10.1016/j.redox.2026.104394},
note = {CC BY},
}
RIS
TY - JOUR
TI - Combination of genetic eNOS deficiency and high-fat diet induces reproducible cardiometabolic HFpEF
AU - Mahmoud H. Elbatreek
AU - Vinayak S. Khodade
AU - Darshan Amin
AU - Miguel Huerta
AU - Timothy D. Allerton
AU - David J. Polhemus
AU - Sanjiv J. Shah
AU - Thomas M. Vondriska
AU - Traci T. Goodchild
AU - David J. Lefer
PY - 2026
DA - 2026/10/30
JO - Redox Biology
DO - 10.1016/j.redox.2026.104394
UR - https://doi.org/10.1016/j.redox.2026.104394
AB - Heart failure with preserved ejection fraction (HFpEF) is a complex, multi-organ cardiometabolic syndrome lacking universally effective therapies. We developed and validated a robust murine model leveraging complete, constitutive genetic endothelial nitric oxide synthase deficiency (eNOS KO) coupled with metabolic stress via a high-fat diet (HFD) in both male and female cohorts. eNOS KO mice subjected to HFD (10 weeks for males; 15 weeks for females) developed a severe and highly reproducible cardiometabolic HFpEF phenotype. Despite preserved left ventricular ejection fraction, both sexes exhibited profound diastolic dysfunction, characterized by elevated E/e’ ratios and left ventricular end-diastolic pressures (LVEDP), alongside severe exercise intolerance. Consistent with the systemic clinical syndrome, pathological remodeling extended to multi-organ damage, featuring prominent cardiac fibrosis, severe hepatic steatosis, and renal tubulointerstitial fibrosis. Finally, chronic administration of the dual GIP/GLP-1 receptor agonist tirzepatide largely reversed the hemodynamic, functional, and systemic fibrotic derangements. In conclusion, this novel eNOS KO mouse + HFD model provides a rapidly developing, highly penetrant, and chemically unconfounded platform that ensures robust HFpEF induction across both sexes. This model can be readily adopted for the investigation of mechanistic insights into HFpEF pathobiology and for the study of novel HFpEF therapeutics.
SN - 2213-2317
ER -