Hyperuricemia-induced endothelial insulin resistance: the nitric oxide connection

• Published in: Pflügers Archiv Vol. 474; no. 1; pp. 83 - 98
• Main Authors: Bahadoran, Zahra, Mirmiran, Parvin, Kashfi, Khosrow, Ghasemi, Asghar
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.01.2022; Springer Nature B.V
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animals; Apoptosis; Biomedical and Life Sciences; Biomedicine; Cell Biology; Drug development; Drug resistance; Endothelial cells; Endothelial Cells - metabolism; Endothelium, Vascular - metabolism; Human Physiology; Humans; Hyperuricemia; Hyperuricemia - complications; Hyperuricemia - metabolism; Insulin; Insulin Resistance; Invited Review; Kinases; Molecular Medicine; Neurosciences; Nitric oxide; Nitric Oxide - metabolism; Nitric-oxide synthase; Oxidative stress; Receptors; Signal transduction; Uric acid; Uric Acid - metabolism; Vasodilation; Endothelial insulin resistance; Hyperuricemia; Uric acid; Nitric oxide
• ISSN: 0031-6768; 1432-2013; 1432-2013
• DOI: 10.1007/s00424-021-02606-2

Hyperuricemia, defined as elevated serum concentrations of uric acid (UA) above 416 µmol L −1 , is related to the development of cardiometabolic disorders, probably via induction of endothelial dysfunction. Hyperuricemia causes endothelial dysfunction via induction of cell apoptosis, oxidative stress, and inflammation; however, it's interfering with insulin signaling and decreased endothelial nitric oxide (NO) availability, resulting in the development of endothelial insulin resistance, which seems to be a major underlying mechanism for hyperuricemia-induced endothelial dysfunction. Here, we elaborate on how hyperuricemia induces endothelial insulin resistance through the disruption of insulin-stimulated endothelial NO synthesis. High UA concentrations decrease insulin-induced NO synthesis within the endothelial cells by interfering with insulin signaling at either the receptor or post-receptor levels (i.e., proximal and distal steps). At the proximal post-receptor level, UA impairs the function of the insulin receptor substrate (IRS) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) in the insulin signaling pathway. At the distal level, high UA concentrations impair endothelial NO synthase (eNOS)-NO system by decreasing eNOS expression and activity as well as by direct inactivation of NO. Clinically, UA-induced endothelial insulin resistance is translated into impaired endothelial function, impaired NO-dependent vasodilation, and the development of systemic insulin resistance. UA-lowering drugs may improve endothelial function in subjects with hyperuricemia.