Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2010 May;25(3):254-62.
doi: 10.1007/s00380-009-1182-x. Epub 2010 May 29.

Caloric Restriction Reverses High-Fat Diet-Induced Endothelial Dysfunction and Vascular Superoxide Production in C57Bl/6 Mice

Affiliations

Caloric Restriction Reverses High-Fat Diet-Induced Endothelial Dysfunction and Vascular Superoxide Production in C57Bl/6 Mice

Juha Ketonen et al. Heart Vessels. .

Abstract

Obesity is frequently associated with endothelial dysfunction. We hypothesized that high-fat feeding dysregulates the balance between endothelial derived nitric oxide and superoxide formation. Furthermore, we examined whether caloric restriction could reverse the detrimental vascular effects related to obesity. Male C57Bl/6 mice were fed with normal-fat diet (fat 17%) or high-fat diet (fat 60%) for 150 days. After establishment of obesity at day 100, a subgroup of obese mice were put on caloric restriction (CR) (70% of ad libitum energy intake) for an additional 50 days. At day 100, aortic rings from obese mice receiving high-fat diet showed impaired endothelium-dependent vasodilation in response to acetylcholine (ACh). Caloric restriction reversed high-fat diet-induced endothelial dysfunction. At day 150, impaired vasodilatory responses to ACh in obese mice without caloric restriction were markedly improved by preincubation with the tetrahydrobiopterin (BH(4)) precursor sepiapterin and L-arginine, a substrate for endothelial nitric oxide synthase (eNOS). Additionally, inhibition of vascular arginase by L-norvaline partially, and superoxide scavenging by Tiron completely, restored endothelial cell function. Obese mice showed increased vascular superoxide production, which was diminished by endothelial denudation, pretreated of the vascular rings with apocynin (an inhibitor of reduced nicotinamide adenine dinucleotide phosphate [NADPH] oxidase), oxypurinol (an inhibitor of xanthine oxidase), N(G)-nitro-L-arginine methyl ester (LNAME; an inhibitor of eNOS), or by adding the BH(4) precursor sepiapterin. Caloric restriction markedly attenuated vascular superoxide production. In obese mice on CR, endothelial denudation increased superoxide formation whereas vascular superoxide production was unaffected by L-NAME. Western blot analysis revealed decreased phosphorylated eNOS (Ser1177)-to-total eNOS expression ratio in obese mice as compared to lean controls, whereas the phospho-eNOS/NOS ratio in obese mice on CR did not differ from the lean controls. In conclusion, the present study suggests that caloric restriction reverses obesity induced endothelial dysfunction and vascular oxidative stress, and underscores the importance of uncoupled eNOS in the pathogenesis.

Similar articles

See all similar articles

Cited by 28 articles

See all "Cited by" articles

References

    1. Free Radic Res Commun. 1988;4(4):259-63 - PubMed
    1. Biochem Biophys Res Commun. 1987 Oct 14;148(1):314-9 - PubMed
    1. Circ Res. 2008 Apr 25;102(8):923-32 - PubMed
    1. Arterioscler Thromb Vasc Biol. 2005 Aug;25(8):1551-7 - PubMed
    1. Arterioscler Thromb Vasc Biol. 2007 Jul;27(7):1632-7 - PubMed

Publication types

MeSH terms

LinkOut - more resources

Feedback