Inorganic nitrate, hypoxia, and the regulation of cardiac mitochondrial respiration - probing the role of PPARα

Horscroft, James A., O'Brien, Katie A., Clark, Anna D., Lindsay, Ross T., Strang Steel, Alice, Procter, Nathan, Devaux, Jules, Frenneaux, Michael, Harridge, Stephen D. R. and Murray, Andrew (2019) Inorganic nitrate, hypoxia, and the regulation of cardiac mitochondrial respiration - probing the role of PPARα. The FASEB Journal, 33 (6). pp. 7563-7577. ISSN 0892-6638

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Dietary inorganic nitrate prevents aspects of cardiac mitochondrial dysfunction induced by hypoxia, although the mechanism is not completely understood. In both heart and skeletal muscle, nitrate increases fatty acid oxidation capacity, and in the latter case, this involves up-regulation of peroxisome proliferator-activated receptor (PPAR)α expression. Here, we investigated whether dietary nitrate modifies mitochondrial function in the hypoxic heart in a PPARα-dependent manner. Wild-type (WT) mice and mice without PPARα (Ppara−/−) were given water containing 0.7 mM NaCl (control) or 0.7 mM NaNO3 for 35 d. After 7 d, mice were exposed to normoxia or hypoxia (10% O2) for the remainder of the study. Mitochondrial respiratory function and metabolism were assessed in saponin-permeabilized cardiac muscle fibers. Environmental hypoxia suppressed mass-specific mitochondrial respiration and additionally lowered the proportion of respiration supported by fatty acid oxidation by 18% (P < 0.001). This switch away from fatty acid oxidation was reversed by nitrate treatment in hypoxic WT but not Ppara−/− mice, indicating a PPARα-dependent effect. Hypoxia increased hexokinase activity by 33% in all mice, whereas lactate dehydrogenase activity increased by 71% in hypoxic WT but not Ppara−/− mice. Our findings indicate that PPARα plays a key role in mediating cardiac metabolic remodeling in response to both hypoxia and dietary nitrate supplementation.

Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: LivePure Connector
Date Deposited: 03 Apr 2019 14:30
Last Modified: 21 Apr 2023 00:00
DOI: 10.1096/fj.201900067R

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