---
title: "Sex and NOS inhibition shape distinct cardiac responses to cardiometabolic stress in older mice"
id: "biorxiv-6-nitric-oxide-synthase-inhibition-and-biological-sex-define-different-cardiac"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-6-nitric-oxide-synthase-inhibition-and-biological-sex-define-different-cardiac"
content_type: "clinical_feed_article"
specialty: "Cardiology"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.08.28.747952v1?rss=1"
published_at: "2026-09-03T12:00:00.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Sex and NOS inhibition shape distinct cardiac responses to cardiometabolic stress in older mice
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-6-nitric-oxide-synthase-inhibition-and-biological-sex-define-different-cardiac
- **Specialty:** [Cardiology](https://medichelpline.com/clinical-feed/cardiology.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.08.28.747952v1?rss=1)
- **Published At:** 2026-09-03T12:00:00.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Preclinical study examined how **biological sex** and graded inhibition of **nitric oxide synthase (NOS)** influence cardiac outcomes in older C57BL/6J mice subjected to cardiometabolic stress (high-fat diet, HFD). - Older male and female mice (>24 weeks) received HFD plus either low-dose or high-dose NOS inhibition using N(ω)-nitro-L-arginine methyl ester (**L-NAME**) for 15 weeks; low-dose L-NAME (0.3 g/L) was used only in females, high-dose (0.5 g/L) in both sexes. - Female mice given low-dose L-NAME+HFD developed a **HFpEF-like** phenotype: impaired diastolic function, exercise intolerance, and preserved systolic function. - Increasing NOS inhibition in females did not further worsen diastolic dysfunction but triggered activation of inflammatory and cellular stress transcriptional pathways in the heart. - Male mice receiving high-dose L-NAME+HFD developed hypertension, elevated ventricular pressures and reduced systolic function consistent with a **HFrEF-like** phenotype. - Despite divergent functional phenotypes between sexes, circulating lipidomic profiling showed broadly conserved remodeling of **sphingolipid** and **phospholipid** classes, with sex-specific alterations in phosphatidylinositol and lysophosphatidylcholine species. - Transcriptomic analyses found shared regulation across sexes of extracellular matrix, calcium-handling and metabolic pathways; greater NOS inhibition associated with transcriptional signatures of inflammatory signaling, cellular stress responses and mitochondrial homeostasis. - Authors conclude that cardiometabolic stress yields multiple possible cardiac remodeling trajectories rather than a single HF phenotype, and that sex and NOS inhibition dose direct distinct functional and molecular outcomes. - No competing interests were declared by the authors in the source document.
## Clinical Analysis & Structured Key Points
Nitric oxide synthase inhibition and biological sex define different cardiac responses to cardiometabolic stress in older mice. | bioRxiv Skip to main content New Results Nitric oxide synthase inhibition and biological sex define different cardiac responses to cardiometabolic stress in older mice. View ORCID Profile June M Sun , View ORCID Profile Alejandro Torres Riquileme , Joshua Hor , View ORCID Profile Daniel G. Donner , Helen Kiriazis , Shannen M Walker , Simon Bond , Natalie A Mellet , View ORCID Profile Peter J Meikle , View ORCID Profile Adam C Parslow , View ORCID Profile Michael LH Huang , Monica Kanki , View ORCID Profile Brian G Drew , Yow Keat Tham , View ORCID Profile Julie R McMullen , View ORCID Profile Morag J. Young doi: https://doi.org/10.64898/2026.08.28.747952 June M Sun 1 Baker Heart and Diabetes Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for June M Sun Alejandro Torres Riquileme 1 Baker Heart and Diabetes Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Alejandro Torres Riquileme Joshua Hor 1 Baker Heart and Diabetes Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Daniel G. Donner 1 Baker Heart and Diabetes Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Daniel G. Donner Helen Kiriazis 1 Baker Heart and Diabetes Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Shannen M Walker 1 Baker Heart and Diabetes Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Simon Bond 2 Baker Heart & Diabetes Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Natalie A Mellet 1 Baker Heart and Diabetes Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Peter J Meikle 1 Baker Heart and Diabetes Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Peter J Meikle Adam C Parslow 1 Baker Heart and Diabetes Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Adam C Parslow Michael LH Huang 3 University of Sydney; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Michael LH Huang Monica Kanki 1 Baker Heart and Diabetes Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Brian G Drew 1 Baker Heart and Diabetes Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Brian G Drew Yow Keat Tham 1 Baker Heart and Diabetes Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site Julie R McMullen 4 Heart Research Institute Ltd Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Julie R McMullen Morag J. Young 1 Baker Heart and Diabetes Institute; Find this author on Google Scholar Find this author on PubMed Search for this author on this site ORCID record for Morag J. Young For correspondence: morag.young{at}baker.edu.au Abstract Info/History Metrics Preview PDF 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(ω)-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. Competing Interest Statement The authors have declared no competing interest. Copyright The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license . Back to top Previous Next Posted September 03, 2026. Download PDF Email Thank you for your interest in spreading the word about bioRxiv. NOTE: Your email address is requested solely to identify you as the sender of this article. Your Email * Your Name * Send To * Enter multiple addresses on separate lines or separate them with commas. You are going to email the following Nitric oxide synthase inhibition and biological sex define different cardiac responses to cardiometabolic stress in older mice. Message Subject (Your Name) has forwarded a page to you from bioRxiv Message Body (Your Name) thought you would like to see this page from the bioRxiv website. Your Personal Message CAPTCHA This question is for testing whether or not you are a human visitor and to prevent automated spam submissions. Share Nitric oxide synthase inhibition and biological sex define different cardiac responses to cardiometabolic stress in older mice. June M Sun , Alejandro Torres Riquileme , Joshua Hor , Daniel G. Donner , Helen Kiriazis , Shannen M Walker , Simon Bond , Natalie A Mellet , Peter J Meikle , Adam C Parslow , Michael LH Huang , Monica Kanki , Brian G Drew , Yow Keat Tham , Julie R McMullen , Morag J. Young bioRxiv 2026.08.28.747952; doi: https://doi.org/10.64898/2026.08.28.747952 Share This Article: Copy Citation Tools Nitric oxide synthase inhibition and biological sex define different cardiac responses to cardiometabolic stress in older mice. June M Sun , Alejandro Torres Riquileme , Joshua Hor , Daniel G. Donner , Helen Kiriazis , Shannen M Walker , Simon Bond , Natalie A Mellet , Peter J Meikle , Adam C Parslow , Michael LH Huang , Monica Kanki , Brian G Drew , Yow Keat Tham , Julie R McMullen , Morag J. 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