Asymmetric dimethylarginine (ADMA) elevation and arginase up‐regulation contribute to endothelial dysfunction related to insulin resistance in rats and morbidly obese humans

Key points The presence of insulin resistance (IR) is determinant for endothelial dysfunction associated with obesity. Although recent studies have implicated the involvement of mitochondrial superoxide and inflammation in the defective nitric oxide (NO)‐mediated responses and subsequent endothelial...

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Published in:The Journal of physiology 2016-06, Vol.594 (11), p.3045-3060
Main Authors: El Assar, Mariam, Angulo, Javier, Santos‐Ruiz, Marta, Ruiz de Adana, Juan Carlos, Pindado, María Luz, Sánchez‐Ferrer, Alberto, Hernández, Alberto, Rodríguez‐Mañas, Leocadio
Format: Article
Language:English
Subjects:
Adipose Tissue - drug effects
Adipose Tissue - metabolism
Adipose Tissue and Obesity
Adult
Aged
Animals
Arginase - antagonists & inhibitors
Arginase - metabolism
Arginine - analogs & derivatives
Arginine - metabolism
Arginine - pharmacology
Cardiovascular
Dose-Response Relationship, Drug
Endocrine and Metabolic Conditons, Disorders and Treatments
Endothelium, Vascular - drug effects
Endothelium, Vascular - metabolism
Enzyme Inhibitors - pharmacology
Female
Humans
Insulin resistance
Insulin Resistance - physiology
Male
Middle Aged
Nitric oxide
Obesity
Obesity, Morbid - metabolism
Organ Culture Techniques
Rats
Rats, Sprague-Dawley
Research Paper
Rodents
Up-Regulation - drug effects
Up-Regulation - physiology
Vasculature
Vasodilation - drug effects
Vasodilation - physiology
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Summary:Key points The presence of insulin resistance (IR) is determinant for endothelial dysfunction associated with obesity. Although recent studies have implicated the involvement of mitochondrial superoxide and inflammation in the defective nitric oxide (NO)‐mediated responses and subsequent endothelial dysfunction in IR, other mechanisms could compromise this pathway. In the present study, we assessed the role of asymmetric dimethylarginine (ADMA) and arginase with respect to IR‐induced impairment of endothelium‐dependent vasodilatation in human morbid obesity and in a non‐obese rat model of IR. We show that both increased ADMA and up‐regulated arginase are determinant factors in the alteration of the l‐arginine/NO pathway associated with IR in both models and also that acute treatment of arteries with arginase inhibitor or with l‐arginine significantly alleviate endothelial dysfunction. These results help to expand our knowledge regarding the mechanisms of endothelial dysfunction that are related to obesity and IR and establish potential therapeutic targets for intervention. Insulin resistance (IR) is determinant for endothelial dysfunction in human obesity. Although we have previously reported the involvement of mitochondrial superoxide and inflammation, other mechanisms could compromise NO‐mediated responses in IR. We evaluated the role of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) and arginase with respect to IR‐induced impairment of l‐arginine/NO‐mediated vasodilatation in human morbid obesity and in a non‐obese rat model of IR. Bradykinin‐induced vasodilatation was evaluated in microarteries derived from insulin‐resistant morbidly obese (IR‐MO) and non‐insulin‐resistant MO (NIR‐MO) subjects. Defective endothelial vasodilatation in IR‐MO was improved by l‐arginine supplementation. Increased levels of ADMA were detected in serum and adipose tissue from IR‐MO. Serum ADMA positively correlated with IR score and negatively with pD2 for bradykinin. Gene expression determination by RT‐PCR revealed not only the decreased expression of ADMA degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH)1/2 in IR‐MO microarteries, but also increased expression of arginase‐2. Arginase inhibition improved endothelial vasodilatation in IR‐MO. Analysis of endothelial vasodilatation in a non‐obese IR model (fructose‐fed rat) confirmed an elevation of circulating and aortic ADMA concentrations, as well as reduced DDAH aortic content and increased a
ISSN:0022-3751
1469-7793
DOI:10.1113/JP271836