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000301272 041__ $$aEnglish
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000301272 1001_ $$00000-0003-0114-560X$$aPepin, Mark E$$b0
000301272 245__ $$aMitochondrial NNT Promotes Diastolic Dysfunction in Cardiometabolic HFpEF.
000301272 260__ $$aNew York, NY$$bAssoc.$$c2025
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000301272 500__ $$a2025 Jun 6;136(12):1564-1578
000301272 520__ $$aClinical 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.
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000301272 650_7 $$2Other$$aNG-nitroarginine methyl ester
000301272 650_7 $$2Other$$afibrosis
000301272 650_7 $$2Other$$agenetic therapy
000301272 650_7 $$2Other$$aheart failure
000301272 650_7 $$2Other$$aoxidative stress
000301272 7001_ $$00009-0003-1522-3848$$aKonrad, Philipp J M$$b1
000301272 7001_ $$aNazir, Sumra$$b2
000301272 7001_ $$00000-0002-0689-7926$$aBazgir, Farhad$$b3
000301272 7001_ $$00000-0003-3694-4559$$aMaack, Christoph$$b4
000301272 7001_ $$aNickel, Alexander$$b5
000301272 7001_ $$00000-0001-5969-4690$$aGorman, Joshua$$b6
000301272 7001_ $$00000-0001-6946-9825$$aHohl, Mathias$$b7
000301272 7001_ $$00009-0002-7405-8064$$aSchreiter, Friederike$$b8
000301272 7001_ $$aDewenter, Matthias$$b9
000301272 7001_ $$0P:(DE-He78)5c3fb2db99f4cb5ee64d78f2d458d032$$ade Britto Chaves Filho, Adriano$$b10$$udkfz
000301272 7001_ $$0P:(DE-He78)94ae391f53fb9285e1b68f9930615af1$$aSchulze, Almut$$b11$$udkfz
000301272 7001_ $$00000-0001-5689-3571$$aKarlstaedt, Anja$$b12
000301272 7001_ $$00000-0001-7611-378X$$aFrey, Norbert$$b13
000301272 7001_ $$00000-0001-6380-1209$$aSeidman, Christine$$b14
000301272 7001_ $$00000-0002-9082-3566$$aSeidman, Jonathan$$b15
000301272 7001_ $$00000-0002-2322-2699$$aBacks, Johannes$$b16
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