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| Item Type: | Article |
|---|---|
| Title: | Mitochondrial NNT promotes diastolic dysfunction in cardiometabolic HFpEF |
| Creators: |
Pepin, M.E.  ORCID: https://orcid.org/0000-0003-0114-560X, Konrad, P.J.M. ORCID: https://orcid.org/0009-0003-1522-3848, Nazir, S., Bazgir, F. ORCID: https://orcid.org/0000-0002-0689-7926, Maack, C. ORCID: https://orcid.org/0000-0003-3694-4559, Nickel, A., Gorman, J. ORCID: https://orcid.org/0000-0001-5969-4690, Hohl, M. ORCID: https://orcid.org/0000-0001-6946-9825, Schreiter, F. ORCID: https://orcid.org/0009-0002-7405-8064, Dewenter, M., de Britto Chaves Filho, A., Schulze, A. ORCID: https://orcid.org/0000-0002-8199-6422, Karlstaedt, A. ORCID: https://orcid.org/0000-0001-5689-3571, Frey, N. ORCID: https://orcid.org/0000-0001-7611-378X, Seidman, C. ORCID: https://orcid.org/0000-0001-6380-1209, Seidman, J. ORCID: https://orcid.org/0000-0002-9082-3566 and Backs, J. ORCID: https://orcid.org/0000-0002-2322-2699
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| Abstract: | BACKGROUND: Clinical management of heart failure with preserved ejection fraction (HFpEF) is hindered by a lack of disease-modifying therapies capable of altering its distinct pathophysiology. Despite the widespread implementation of a 2-hit model of cardiometabolic HFpEF to inform precision therapy, which utilizes ad libitum high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester, we observe that C57BL6/J mice exhibit less cardiac diastolic dysfunction in response to high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester. METHODS: Genetic strain-specific single-nucleus transcriptomic analysis identified disease-relevant genes that enrich oxidative metabolic pathways within cardiomyocytes. Because C57BL/6J mice are known to harbor a loss-of-function mutation affecting the inner mitochondrial membrane protein Nnt (nicotinamide nucleotide transhydrogenase), we used an isogenic model of Nnt loss-of-function to determine whether intact NNT is necessary for the pathological cardiac manifestations of high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester. Twelve-week-old mice cross-bred to isolate wild-type (Nnt(+/+9) or loss-of-function (Nnt(-/-)) Nnt in the C57BL/6N background were challenged with high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester for 9 weeks (n=6-10). RESULTS: Nnt(+/+) mice exhibited impaired ventricular diastolic relaxation and pathological remodeling, as assessed via E/e' (42.8 versus 21.5, P=1.2×10(-10)), E/A (2.3 versus 1.4, P=4.1×10(-2)), diastolic stiffness (0.09 versus 0.04 mm Hg/μL, P=5.1×10(-3)), and myocardial fibrosis (P=2.3×10(-2)). Liquid chromatography and mass spectroscopy exposed a 40.0% reduction in NAD(+) (P=8.4×10(-3)) and a 38.8% reduction in glutathione:GSSG (P=2.6×10(-2)) among Nnt(+/+) mice after high-fat diet and 0.5% N(ω)-nitro-L-arginine methyl ester feeding. Using single-nucleus ligand-receptor analysis, we implicate Fgf1 (fibroblast growth factor 1) as a putative NNT-dependent mediator of cardiomyocyte-to-fibroblast signaling of myocardial fibrosis. CONCLUSIONS: Together, these findings underscore the pivotal role of mitochondrial dysfunction in HFpEF pathogenesis, implicating both NNT and Fgf1 as novel therapeutic targets. |
| Keywords: | Fibrosis, Genetic Therapy, Heart Failure, NG-Nitroarginine Methyl Ester, Oxidative Stress, Animals, Mice |
| Source: | Circulation Research |
| ISSN: | 0009-7330 |
| Publisher: | American Heart Association |
| Volume: | 136 |
| Number: | 12 |
| Page Range: | 1564-1578 |
| Date: | 6 June 2025 |
| Official Publication: | https://doi.org/10.1161/CIRCRESAHA.125.326154 |
| PubMed: | View item in PubMed |
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