Keller 2018 Oxid Med Cell Longev

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Keller AC, Knaub LA, Scalzo RL, Hull SE, Johnston AE, Walker LA, Reusch JEB (2018) Sepiapterin improves vascular reactivity and insulin-stimulated glucose in wistar rats. Oxid Med Cell Longev 2018:7363485.

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Keller AC, Knaub LA, Scalzo RL, Hull SE, Johnston AE, Walker LA, Reusch JEB (2018) Oxid Med Cell Longev

Abstract: In the vasculature, sedentary behavior leads to endothelial abnormalities, resulting in elevated cardiovascular disease risk. Endothelial nitric oxide synthase (eNOS) aberrations characterize endothelial dysfunction; eNOS also regulates mitochondrial function. We hypothesized that sepiapterin (a precursor to eNOS cofactor tetrahydrobiopterin (BH4)) supplementation would improve endothelium-dependent vascular relaxation in sedentary animals via modulation of NOS function and mitochondrial activity. Sedentary male Wistar rats were fed ad libitum for a total of 10 weeks. Sepiapterin was administered in diet during the final 5 weeks. Intraperitoneal insulin and glucose tolerance tests (IP-ITT/IP-GTT) were conducted at baseline and endpoint. Aorta was assessed for vasoreactivity and mitochondrial respiration. Insulin tolerance, determined by IP-ITT, significantly improved in rats treated with sepiapterin (p < 0.05, interaction of time and treatment). Acetylcholine- (ACh-) driven vasodilation was significantly greater in aorta from sepiapterin-treated rats as compared with control (76.4% versus 54.9% of phenylephrine contraction at 20 μM ACh, p < 0.05). Sepiapterin treatment resulted in significantly elevated state 3 (9.00 oxygen pmol/sec∗mg versus 8.17 oxygen pmol/sec∗mg, p < 0.05) and 4 (7.28 oxygen pmol/sec∗mg versus 5.86 oxygen pmol/sec∗mg, p < 0.05) aortic mitochondrial respiration with significantly lower respiratory control ratio (p < 0.05) during octanoylcarnitine driven respiration. Vasodilation and insulin sensitivity were improved through targeting NOS via sepiapterin supplementation.


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Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Cardiovascular 

Organism: Rat  Tissue;cell: Endothelial;epithelial;mesothelial cell  Preparation: Permeabilized tissue  Enzyme: Complex I, Complex II;succinate dehydrogenase, Complex III, Complex IV;cytochrome c oxidase, Complex V;ATP synthase 

Coupling state: LEAK, OXPHOS, ET  Pathway: F, N, NS  HRR: Oxygraph-2k 

Labels, 2018-10