Genetic and Pharmacological Manipulation of Urotensin II Ameliorate the Metabolic and Atherosclerosis Sequalae in Mice

• Published in: Arteriosclerosis, thrombosis, and vascular biology Vol. 32; no. 8; pp. 1809 - 1816
• Main Authors: You, Zhipeng, Genest, Jacques, Barrette, Pierre-Olivier, Hafiane, Anouar, Behm, David J, D’Orleans-Juste, Pedro, Schwertani, Adel Giaid
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Heart Association, Inc 01-08-2012; Lippincott Williams & Wilkins
• Subjects: Animals; Apolipoproteins E - physiology; Associated diseases and complications; Atherosclerosis (general aspects, experimental research); Atherosclerosis - etiology; Atherosclerosis - prevention & control; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Diabetes. Impaired glucose tolerance; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Female; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Sulfonamides - pharmacology; Urotensins - blood; Urotensins - physiology; Hypertension; Obesity; Pancreatic hormone; hyperlipidemia; Rodentia; Nutrition disorder; Metabolic diseases; Lipids; Cardiovascular disease; Insulin; mice; Vascular disease; Vertebrata; Mammalia; Mouse; Animal; Atherosclerosis; Hyperlipemia; Dyslipemia; Nutritional status; tolerance
• ISSN: 1079-5642; 1524-4636
• DOI: 10.1161/ATVBAHA.112.252973

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).
CONCLUSION—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.