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(Circulation Research. 2009;105:686.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Urotensin II Receptor Knockout Mice on an ApoE Knockout Background Fed a High-Fat Diet Exhibit an Enhanced Hyperlipidemic and Atherosclerotic Phenotype

Nicolas Bousette, Pedro D'Orleans-Juste, Robert S. Kiss, Zhipeng You, Jacques Genest, Wisam Al-Ramli, Salman T. Qureshi, Anthony Gramolini, David Behm, Eliot H. Ohlstein, Stephen M. Harrison, Stephen A. Douglas, Adel Giaid

From the Division of Cardiology and Department of Medicine (N.B., R.S.K., Z.Y., J.G., W.A.-R., S.T.Q., A.G.), Montreal General Hospital, McGill University Health Center, Quebec, Canada; Sherbrooke Institute of Pharmacology (P.D.-J.), Quebec, Canada; Cardiovascular Pharmacology, Cardiovascular and Urogenital-CEDD (D.B., E.H.O., S.A.D.), GlaxoSmithKline, King of Prussia, Pa; the Department of Comparative Genomics (S.M.H.), GlaxoSmithKline, Harlow, UK; and the Department of Physiology (A.G.), University of Toronto, Ontario, Canada.

Correspondence to Dr Adel Giaid, Montreal General Hospital, Suite L3-109, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada. E-mail adel.giaid{at}mcgill.ca

Rationale: Expression of the vasoactive peptide Urotensin II (UII) is elevated in a number of cardiovascular diseases.

Objective: Here, we sought to determine the effect of UII receptor (UT) gene deletion in a mouse model of atherosclerosis.

Methods and Results: UT knockout (KO) mice were crossed with ApoE KO mice to generate UT/ApoE double knockout (DKO) mice. Mice were placed on a high-fat Western-type diet for 12 weeks. We evaluated the degree of atherosclerosis and hepatic steatosis by histology. In addition, serum glucose, insulin, and lipids were determined. DKO mice exhibited significantly increased atherosclerosis compared to ApoE KO mice (P<0.05). This was associated with a significant increase in serum insulin and lipids (P<0.001) but a decrease in hepatic steatosis (P<0.001). UT gene deletion led to a significant increase in systolic pressure and pulse pressure. RT-PCR and immunoblot analyses showed significant reductions in hepatic scavenger receptors, nuclear receptors, and acyl-CoA:cholesterol acyltransferase (ACAT1) expression in DKO mice. UII induced a significant increase in intracellular cholesteryl ester formation in primary mouse hepatocytes, which was blocked by the MEK inhibitor, PD98059. Hepatocytes of UTKO mice showed a significant reduction in lipoprotein uptake compared to wild-type mice.

Conclusions: We propose that UT gene deletion in an ApoE-deficient background promotes downregulation of ACAT1, which in turn attenuates hepatic lipoprotein receptor-mediated uptake and lipid transporter expression. As the liver is the main organ for uptake of lipoprotein-derived lipids, DKO leads to an increase in hyperlipidemia, with a concomitant decrease in hepatic steatosis, and consequently increased atherosclerotic lesion formation. Furthermore, the hypertension associated with UT gene deletion is likely to contribute to the increased atherosclerotic burden.

Key Words: urotensin II receptor • aorta • liver • lipid • hypercholesterolemia • ACAT