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

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 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 NaNO 3 for 35 d. After 7 d, mice were exposed to normoxia or hypoxia (10% O 2 ) 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.—Horscroft, J. A., O’Brien, K. A., Clark, A. D., Lindsay, R. T., Steel, A. S., Procter, N. E. K., Devaux, J., Frenneaux, M., Harridge, S. D. R., Murray, A. J. Inorganic nitrate, hypoxia, and the regulation of cardiac mitochondrial respiration—probing the role of PPARα.

PDE9 Inhibition Activates PPARα to Stimulate Mitochondrial Fat Metabolism and Reduce Cardiometabolic Syndrome

“…These are felt to converge on transcriptional regulators PPAR gamma co-activator 1α (PGC1α) and PPARα (14, 15) to control metabolism. PKG-dependent PPARα activation has been previously linked to mitochondrial protection against hypoxia-induced cardiac injury (19) and increased FA oxidation and catabolism in skeletal muscle (16) , though not with countering obesity. To our knowledge, none of these kinase or lipase effectors of PKG modulation have been shown to confer a sexual dimorphism on metabolic signaling.…”

“…PKG can be exogenously activated either by stimulating cGMP synthesis or suppressing its hydrolysis via specific phosphodiesterases (PDEs), and while there is shared downstream signaling, there are also many differences due to intra-cellular compartmentation and cell/organ specificity (17) . Stimulatory approaches include exogenous natural or synthetic NPs (18) , nitrates/nitrites (19) , and direct soluble guanylate cyclase stimulators (20) . However, each has limitations for chronic obesity therapy as they act rapidly, are short-lived and can potently lower blood pressure from vasodilation.…”

Altered mitochondrial metabolism in the insulin‐resistant heart

“…Additionally, mitochondrial biogenesis occurred with higher doses of nitrate supplementation via the activation of PGC‐1α . Similarly, nitrate supplementation increased FAO capacity in rodent hearts in a PPARα‐dependent manner . Owing to its effects on mitochondrial FAO capacity, dietary nitrate supplementation might be beneficial in metabolic syndrome and T2DM both systemically and to the heart in particular.…”

“…215 Similarly, nitrate supplementation increased FAO capacity in rodent hearts in a PPARα-dependent manner. 216,217 Owing to its effects on mitochondrial FAO capacity, dietary nitrate supplementation might be beneficial in metabolic syndrome and T2DM both systemically and to the heart in particular. This may be the case even when the primary cause of the metabolic condition is not deficient expression/activity of eNOS, and this deserves further investigation in models of T2DM beyond the eNOS knockout mouse.…”

Comparative Analysis of Metabolic Differences of Jersey Cattle in Different High-Altitude Areas

“…Recent studies have found that people from low altitude to high altitude will cause significant remodeling of tissue metabolism, as well as changes in the level of circulating metabolism ( 9 , 10 ). Hypoxia can inhibit the oxidative metabolism of heart ( 11 ) and skeletal muscle ( 12 ), reduce the ability of fatty acid oxidation ( 13 ), and increase glycolysis ( 14 ) in rodents and non-plateau native people. Based on miRNA and proteomics, we found that Jersey cattle adapt to high-altitude hypoxia by regulating inflammatory homeostasis ( 15 ).…”