{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T06:54:03Z","timestamp":1792652043231,"version":"4.5.0"},"reference-count":68,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"12","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2025,6,6]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>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[\u03c9]-nitro-L-arginine methyl ester), we observe that C57BL6\/J mice exhibit less cardiac diastolic dysfunction in response to HFD+L-NAME.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic toggle=\"yes\">Nnt<\/jats:italic>\n                      (nicotinamide nucleotide transhydrogenase), we established an isogenic model of\n                      <jats:italic toggle=\"yes\">Nnt<\/jats:italic>\n                      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 (\n                      <jats:italic toggle=\"yes\">Nnt<\/jats:italic>\n                      <jats:sup>+\/+<\/jats:sup>\n                      ) or loss-of-function (\n                      <jats:italic toggle=\"yes\">Nnt<\/jats:italic>\n                      <jats:sup>\u2212<\/jats:sup>\n                      <jats:sup>\/<\/jats:sup>\n                      <jats:sup>\u2212<\/jats:sup>\n                      )\n                      <jats:italic toggle=\"yes\">Nnt<\/jats:italic>\n                      in the C57BL\/6N background were challenged with HFD+L-NAME for 9 weeks (N=6\u201310).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      <jats:italic toggle=\"yes\">Nnt<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic toggle=\"yes\">+\/+<\/jats:italic>\n                      <\/jats:sup>\n                      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\u2032) ratio (E\/e\u2032) (42.8 versus 21.5,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =1.2\u00d710\n                      <jats:sup>\u2212<\/jats:sup>\n                      <jats:sup>10<\/jats:sup>\n                      ), E\/A (early-to-late mitral inflow velocity ratio) (2.3 versus 1.4,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =4.1\u00d710\n                      <jats:sup>\u2212<\/jats:sup>\n                      <jats:sup>2<\/jats:sup>\n                      ), diastolic stiffness (0.09 versus 0.04 mm\u2005Hg\/\u03bcL,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =5.1\u00d710\n                      <jats:sup>\u2212<\/jats:sup>\n                      <jats:sup>3<\/jats:sup>\n                      ), and myocardial fibrosis (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =2.3\u00d710\n                      <jats:sup>\u2212<\/jats:sup>\n                      <jats:sup>2<\/jats:sup>\n                      ). Liquid chromatography and mass spectroscopy exposed a 40.0% reduction in NAD\n                      <jats:sup>+<\/jats:sup>\n                      (\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =8.4\u00d710\n                      <jats:sup>\u2212<\/jats:sup>\n                      <jats:sup>3<\/jats:sup>\n                      ) and a 38.8% reduction in the ratio of reduced-to-oxidized glutathione (GSH: GSSG,\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                      =2.6\u00d710\n                      <jats:sup>\u2212<\/jats:sup>\n                      <jats:sup>2<\/jats:sup>\n                      ) among\n                      <jats:italic toggle=\"yes\">Nnt<\/jats:italic>\n                      <jats:sup>+\/+<\/jats:sup>\n                      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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>Together, these findings underscore the pivotal role of mitochondrial dysfunction in HFpEF pathogenesis, implicating both NNT and Fgf1 as novel therapeutic targets.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.125.326154","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T05:00:24Z","timestamp":1746766824000},"page":"1564-1578","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":33,"title":["Mitochondrial NNT Promotes Diastolic Dysfunction in Cardiometabolic 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