Nitric oxide synthase inhibition and biological sex define different cardiac responses to cardiometabolic stress in older mice.
- 1Baker Heart and Diabetes Institute
Abstract
Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome associated with ageing, obesity and impaired nitric oxide signalling. Preclinical models often do not capture the sex-specific and cardiometabolic features observed in patients. We hypothesised that biological sex and the degree of nitric oxide synthase (NOS) inhibition would influence development of HFpEF-like versus HFrEF-like phenotypes. Methods and Results: Male and female C57BL/6J mice (>24 weeks) were exposed to a high-fat diet (HFD) combined with low-dose (0.3 g/L; female only) or high-dose (0.5 g/L; male and female) NOS inhibition using N({omega})-nitro-L-arginine methyl ester (L-NAME) for 15 weeks. Female mice receiving low-dose L-NAME+HFD developed a HFpEF-like phenotype characterised by impaired diastolic function, exercise intolerance and preserved systolic function. Increasing NOS inhibition did not worsen diastolic dysfunction but induced inflammatory and stress-associated transcriptional pathways in female hearts. In contrast, male mice given high-dose L-NAME+HFD developed hypertension, elevated ventricular pressures and impaired systolic function, consistent with a HFrEF-like phenotype. Despite different cardiac phenotypes, circulating lipidomic profiling revealed broadly conserved sphingolipid and phospholipid remodelling, with sex-specific regulation of phosphatidylinositol and lysophosphatidylcholine species. Transcriptomic analyses identified shared regulation of extracellular matrix, calcium-handling and metabolic pathways, whereas greater NOS inhibition was associated with transcriptional signatures related to inflammatory signalling, cellular stress responses and mitochondrial homeostasis. Conclusions: Cardiometabolic stress does not produce a uniform HF phenotype. Instead, biological sex and the degree of NOS inhibition direct distinct functional and molecular remodelling trajectories, identifying HFpEF-like dysfunction as one of several potential cardiac responses to cardiometabolic injury.
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BibTeX
@misc{sun2026nitric,
title = {{Nitric oxide synthase inhibition and biological sex define different cardiac responses to cardiometabolic stress in older mice.}},
author = {J. M. Sun and A. T. Riquileme and J. Hor and D. G. Donner and H. Kiriazis and S. M. Walker and S. Bond and N. A. Mellet and P. J. Meikle and A. C. Parslow and M. L. Huang and M. Kanki and B. G. Drew and Y. K. Tham and J. R. McMullen and M. J. Young},
howpublished = {bioRxiv},
year = {2026},
month = aug,
doi = {10.64898/2026.08.28.747952},
url = {https://www.biorxiv.org/content/10.64898/2026.08.28.747952v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Nitric oxide synthase inhibition and biological sex define different cardiac responses to cardiometabolic stress in older mice.
AU - J. M. Sun
AU - A. T. Riquileme
AU - J. Hor
AU - D. G. Donner
AU - H. Kiriazis
AU - S. M. Walker
AU - S. Bond
AU - N. A. Mellet
AU - P. J. Meikle
AU - A. C. Parslow
AU - M. L. Huang
AU - M. Kanki
AU - B. G. Drew
AU - Y. K. Tham
AU - J. R. McMullen
AU - M. J. Young
PY - 2026
DA - 2026/08/28
PB - bioRxiv
DO - 10.64898/2026.08.28.747952
UR - https://www.biorxiv.org/content/10.64898/2026.08.28.747952v1
AB - Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome associated with ageing, obesity and impaired nitric oxide signalling. Preclinical models often do not capture the sex-specific and cardiometabolic features observed in patients. We hypothesised that biological sex and the degree of nitric oxide synthase (NOS) inhibition would influence development of HFpEF-like versus HFrEF-like phenotypes. Methods and Results: Male and female C57BL/6J mice (>24 weeks) were exposed to a high-fat diet (HFD) combined with low-dose (0.3 g/L; female only) or high-dose (0.5 g/L; male and female) NOS inhibition using N({omega})-nitro-L-arginine methyl ester (L-NAME) for 15 weeks. Female mice receiving low-dose L-NAME+HFD developed a HFpEF-like phenotype characterised by impaired diastolic function, exercise intolerance and preserved systolic function. Increasing NOS inhibition did not worsen diastolic dysfunction but induced inflammatory and stress-associated transcriptional pathways in female hearts. In contrast, male mice given high-dose L-NAME+HFD developed hypertension, elevated ventricular pressures and impaired systolic function, consistent with a HFrEF-like phenotype. Despite different cardiac phenotypes, circulating lipidomic profiling revealed broadly conserved sphingolipid and phospholipid remodelling, with sex-specific regulation of phosphatidylinositol and lysophosphatidylcholine species. Transcriptomic analyses identified shared regulation of extracellular matrix, calcium-handling and metabolic pathways, whereas greater NOS inhibition was associated with transcriptional signatures related to inflammatory signalling, cellular stress responses and mitochondrial homeostasis. Conclusions: Cardiometabolic stress does not produce a uniform HF phenotype. Instead, biological sex and the degree of NOS inhibition direct distinct functional and molecular remodelling trajectories, identifying HFpEF-like dysfunction as one of several potential cardiac responses to cardiometabolic injury.
ER -