Mitochondrial NNT promotes diastolic dysfunction in cardiometabolic HFpEF

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Item Type:	Article
Title:	Mitochondrial NNT promotes diastolic dysfunction in cardiometabolic HFpEF
Creators Name:	Pepin, M.E., Konrad, P.J.M., Nazir, S., Bazgir, F., Maack, C., Nickel, A., Gorman, J., Hohl, M., Schreiter, F., Dewenter, M., de Britto Chaves Filho, A., Schulze, A., Karlstaedt, A., Frey, N., Seidman, C., Seidman, J. and Backs, J.
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
Date:	9 May 2025
Official Publication:	https://doi.org/10.1161/CIRCRESAHA.125.326154
PubMed:	View item in PubMed

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