Circulation research · 2025
Mitochondrial NNT Promotes Diastolic Dysfunction in Cardiometabolic HFpEF.
СтатьяНазвание и аннотация: Перевод в очереди
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Pepin Mark E, Konrad Philipp J M, Nazir Sumra, Bazgir Farhad, Maack Christoph, Nickel Alexander, Gorman Joshua M, Hohl Mathias, Schreiter Friederike, Dewenter Matthias, de Britto Chaves Filho Adriano, Schulze Almut, Karlstaedt Anja, Frey Norbert, Seidman Christine E, Seidman Jonathan G, Backs Johannes
Аннотация
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 HFD+L-NAME (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 HFD+L-NAME.
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 established an isogenic model of Nnt loss-of-function to determine whether intact NNT is necessary for the pathological cardiac manifestations of HFD+L-NAME. Twelve-week-old mice cross-bred to isolate wild-type (Nnt+/+) or loss-of-function (Nnt-/-) Nnt in the C57BL/6N background were challenged with HFD+L-NAME for 9 weeks (N=6-10).
RESULTS: Nnt+/+ mice exhibited impaired ventricular diastolic relaxation and pathological remodeling, as assessed via noninvasive echocardiographic quantification of early diastolic pulse-wave velocity (E) to mitral annular velocity (e') ratio (E/e') (42.8 versus 21.5, P=1.2×10-10), E/A (early-to-late mitral inflow velocity ratio) (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 the ratio of reduced-to-oxidized glutathione (GSH: GSSG, P=2.6×10-2) among Nnt+/+ mice after HFD+L-NAME 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 in 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.
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 established an isogenic model of Nnt loss-of-function to determine whether intact NNT is necessary for the pathological cardiac manifestations of HFD+L-NAME. Twelve-week-old mice cross-bred to isolate wild-type (Nnt+/+) or loss-of-function (Nnt-/-) Nnt in the C57BL/6N background were challenged with HFD+L-NAME for 9 weeks (N=6-10).
RESULTS: Nnt+/+ mice exhibited impaired ventricular diastolic relaxation and pathological remodeling, as assessed via noninvasive echocardiographic quantification of early diastolic pulse-wave velocity (E) to mitral annular velocity (e') ratio (E/e') (42.8 versus 21.5, P=1.2×10-10), E/A (early-to-late mitral inflow velocity ratio) (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 the ratio of reduced-to-oxidized glutathione (GSH: GSSG, P=2.6×10-2) among Nnt+/+ mice after HFD+L-NAME 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 in 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.