Urotensin II receptor knockout mice on an ApoE knockout background fed a high-fat diet exhibit an enhanced hyperlipidemic and atherosclerotic phenotype.
BACKGROUND
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.


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.
Bousette
Nicolas
N
Division of Cardiology and Department of Medicine, Montreal General Hospital, McGill University Health Center, Quebec, Canada.
D'Orleans-Juste
Pedro
P
Kiss
Robert S
RS
You
Zhipeng
Z
Genest
Jacques
J
Al-Ramli
Wisam
W
Qureshi
Salman T
ST
Gramolini
Anthony
A
Behm
David
D
Ohlstein
Eliot H
EH
Harrison
Stephen M
SM
Douglas
Stephen A
SA
Giaid
Adel
A
D000101:Acetyl-CoA C-Acetyltransferase / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D001786:Blood Glucose / Q000378:metabolism; D001794:Blood Pressure; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D005234:Fatty Liver / Q000378:metabolism / Q000517:prevention & control; D005838:Genotype; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010641:Phenotype; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics; D051116:Receptors, Scavenger / Q000378:metabolism; D013997:Time Factors; D014579:Urotensins / Q000378:metabolism*
D001057:Apolipoproteins E; D001786:Blood Glucose; D002788:Cholesterol Esters; D004041:Dietary Fats; D007328:Insulin; D008055:Lipids; D047428:Protein Kinase Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D043562:Receptors, G-Protein-Coupled; D051116:Receptors, Scavenger; D014579:Urotensins; C512325:urotensin II receptor, mouse; C029677:urotensin II; C506641:Acat1 protein, mouse; D000101:Acetyl-CoA C-Acetyltransferase; D020929:Mitogen-Activated Protein Kinase Kinases