Genetic and pharmacological manipulation of urotensin II ameliorate the metabolic and atherosclerosis sequalae in mice.

OBJECTIVE: Urotensin II (UII) is a potent vasoactive peptide that binds to the urotensin receptor-coupled receptor-14 (known as UT) and exerts a wide range of actions in humans and experimental animals. We tested the hypothesis that UII gene deletion or UT blockade ameliorate experimental atherosclerosis. METHODS AND RESULTS: We observed a significant reduction in weight gain, visceral fat, blood pressure, circulating plasma lipids, and proatherogenic cytokines and improvement of glucose tolerance in UII knockout mice compared with wild type (P<0.05). Deletion of UII after an apolipoprotein E knockout resulted in a significant reduction in serum cytokines, adipokines, and aortic atherosclerosis compared with apolipoprotein E knockout mice. Similarly, treatment of apolipoprotein E knockout mice fed on high-fat diet with the UT antagonist SB657510A reduced weight gain, visceral fat, and hyperlipidemia and improved glucose tolerance (P<0.05) and attenuated the initiation and progression of atherosclerosis. The UT antagonist also decreased aortic extracellular signal-regulated kinase 1/2 phosphorylation and oxidant formation and serum level of cytokines (P<0.05). CONCLUSIONS: These findings demonstrate for the first time the role of UII gene deletion in atherosclerosis and suggest that the use of pharmaceutical agents aimed at blocking the UII pathway may provide a novel approach in the treatment of atherosclerosis and its associated precursors such as obesity, hyperlipidemia, diabetes mellitus, and hypertension.

A closer look at the role of urotensin II in the metabolic syndrome.

Urotensin II (UII) is a vasoactive peptide that was first discovered in the teleost fish, and later in mammals and humans. UII binds to the G protein coupled receptor GPR14 (now known as UT). UII mediates important physiological and pathological actions by interacting with its receptor. The metabolic syndrome (MetS) is described as cluster of factors such as obesity, dyslipidemia, hypertension, and insulin resistance (IR), further leading to development of type 2 diabetes mellitus and cardiovascular diseases. UII levels are upregulated in patients with the MetS. Evidence directly implicating UII in every risk factor of the MetS has been accumulated. The mechanism that links the different aspects of the MetS relies primarily on IR and inflammation. By directly modulating both of these factors, UII is thought to play a central role in the pathogenesis of the MetS. Moreover, UII also plays an important role in hypertension and hyperlipidemia thereby contributing to cardiovascular complications associated with the MetS.