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

JA Horscroft, Stephen D R Harridge, KA O'Brien, AD Clark, RT Lindsay, AS Steel, NEK Procter, J Devaux, M Frenneaux, AJ Murray

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

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 involved upregulation of PPARα expression. Here we investigated whether dietary nitrate modifies mitochondrial function in the hypoxic heart in a PPARα-dependent manner. Wild-type and Ppara-/- mice 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 saponinpermeabilised cardiac muscle fibres. 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 wild-type but not Ppara-/- mice, indicating a PPARαdependent effect. Hypoxia increased hexokinase activity by 33% in all mice, whilst lactate dehydrogenase activity increased by 71% in hypoxic wild-type but not Ppara-/- mice. Our findings indicate that PPARα plays a key role in mediating cardiac metabolic remodelling in response to both hypoxia and dietary nitrate supplementation.
Original languageEnglish
Pages (from-to)7563-7577
Number of pages15
JournalTHE FASEB JOURNAL : OFFICIAL PUBLICATION OF THE FEDERATION OF AMERICAN SOCIETIES FOR EXPERIMENTAL BIOLOGY
Volume33
Issue number6
DOIs
Publication statusPublished - 1 Jun 2019

Keywords

  • fatty acids
  • heart
  • metabolism
  • mitochondria

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