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| 001 | 301272 | ||
| 005 | 20250608020920.0 | ||
| 024 | 7 | _ | |a 10.1161/CIRCRESAHA.125.326154 |2 doi |
| 024 | 7 | _ | |a pmid:40340422 |2 pmid |
| 024 | 7 | _ | |a 0009-7330 |2 ISSN |
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| 037 | _ | _ | |a DKFZ-2025-00957 |
| 041 | _ | _ | |a English |
| 082 | _ | _ | |a 610 |
| 100 | 1 | _ | |a Pepin, Mark E |0 0000-0003-0114-560X |b 0 |
| 245 | _ | _ | |a Mitochondrial NNT Promotes Diastolic Dysfunction in Cardiometabolic HFpEF. |
| 260 | _ | _ | |a New York, NY |c 2025 |b Assoc. |
| 336 | 7 | _ | |a article |2 DRIVER |
| 336 | 7 | _ | |a Output Types/Journal article |2 DataCite |
| 336 | 7 | _ | |a Journal Article |b journal |m journal |0 PUB:(DE-HGF)16 |s 1749213719_348 |2 PUB:(DE-HGF) |
| 336 | 7 | _ | |a ARTICLE |2 BibTeX |
| 336 | 7 | _ | |a JOURNAL_ARTICLE |2 ORCID |
| 336 | 7 | _ | |a Journal Article |0 0 |2 EndNote |
| 500 | _ | _ | |a 2025 Jun 6;136(12):1564-1578 |
| 520 | _ | _ | |a 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. |
| 536 | _ | _ | |a 311 - Zellbiologie und Tumorbiologie (POF4-311) |0 G:(DE-HGF)POF4-311 |c POF4-311 |f POF IV |x 0 |
| 588 | _ | _ | |a Dataset connected to CrossRef, PubMed, , Journals: inrepo02.dkfz.de |
| 650 | _ | 7 | |a NG-nitroarginine methyl ester |2 Other |
| 650 | _ | 7 | |a fibrosis |2 Other |
| 650 | _ | 7 | |a genetic therapy |2 Other |
| 650 | _ | 7 | |a heart failure |2 Other |
| 650 | _ | 7 | |a oxidative stress |2 Other |
| 700 | 1 | _ | |a Konrad, Philipp J M |0 0009-0003-1522-3848 |b 1 |
| 700 | 1 | _ | |a Nazir, Sumra |b 2 |
| 700 | 1 | _ | |a Bazgir, Farhad |0 0000-0002-0689-7926 |b 3 |
| 700 | 1 | _ | |a Maack, Christoph |0 0000-0003-3694-4559 |b 4 |
| 700 | 1 | _ | |a Nickel, Alexander |b 5 |
| 700 | 1 | _ | |a Gorman, Joshua |0 0000-0001-5969-4690 |b 6 |
| 700 | 1 | _ | |a Hohl, Mathias |0 0000-0001-6946-9825 |b 7 |
| 700 | 1 | _ | |a Schreiter, Friederike |0 0009-0002-7405-8064 |b 8 |
| 700 | 1 | _ | |a Dewenter, Matthias |b 9 |
| 700 | 1 | _ | |a de Britto Chaves Filho, Adriano |0 P:(DE-He78)5c3fb2db99f4cb5ee64d78f2d458d032 |b 10 |u dkfz |
| 700 | 1 | _ | |a Schulze, Almut |0 P:(DE-He78)94ae391f53fb9285e1b68f9930615af1 |b 11 |u dkfz |
| 700 | 1 | _ | |a Karlstaedt, Anja |0 0000-0001-5689-3571 |b 12 |
| 700 | 1 | _ | |a Frey, Norbert |0 0000-0001-7611-378X |b 13 |
| 700 | 1 | _ | |a Seidman, Christine |0 0000-0001-6380-1209 |b 14 |
| 700 | 1 | _ | |a Seidman, Jonathan |0 0000-0002-9082-3566 |b 15 |
| 700 | 1 | _ | |a Backs, Johannes |0 0000-0002-2322-2699 |b 16 |
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