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@ARTICLE{Pepin:301272,
      author       = {M. E. Pepin and P. J. M. Konrad and S. Nazir and F. Bazgir
                      and C. Maack and A. Nickel and J. Gorman and M. Hohl and F.
                      Schreiter and M. Dewenter and A. de Britto Chaves Filho$^*$
                      and A. Schulze$^*$ and A. Karlstaedt and N. Frey and C.
                      Seidman and J. Seidman and J. Backs},
      title        = {{M}itochondrial {NNT} {P}romotes {D}iastolic {D}ysfunction
                      in {C}ardiometabolic {HF}p{EF}.},
      journal      = {Circulation research},
      volume       = {136},
      number       = {12},
      issn         = {0009-7330},
      address      = {New York, NY},
      publisher    = {Assoc.},
      reportid     = {DKFZ-2025-00957},
      pages        = {1564-1578},
      year         = {2025},
      note         = {2025 Jun 6;136(12):1564-1578},
      abstract     = {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.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+/+) 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).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.Together, these findings underscore the
                      pivotal role of mitochondrial dysfunction in HFpEF
                      pathogenesis, implicating both NNT and Fgf1 as novel
                      therapeutic targets.},
      keywords     = {NG-nitroarginine methyl ester (Other) / fibrosis (Other) /
                      genetic therapy (Other) / heart failure (Other) / oxidative
                      stress (Other)},
      cin          = {A410},
      ddc          = {610},
      cid          = {I:(DE-He78)A410-20160331},
      pnm          = {311 - Zellbiologie und Tumorbiologie (POF4-311)},
      pid          = {G:(DE-HGF)POF4-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40340422},
      doi          = {10.1161/CIRCRESAHA.125.326154},
      url          = {https://inrepo02.dkfz.de/record/301272},
}