Abstract-Human urotensin II (U-II), the most potent vasoconstrictor peptide identified to date, and its receptor (UT) are involved in hypertension and atherosclerosis. Acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT-1) converts intracellular free cholesterol into cholesterol ester (CE) for storage in lipid droplets and plays an important role in the formation of macrophage-derived foam cells in atherosclerotic lesions. We examined the effects of U-II on ACAT-1 expression and CE accumulation in human monocyte-derived macrophages. U-II increased ACAT activity in a concentration-dependent manner after 7 days in monocyte primary culture. Immunoblotting analysis showed that U-II at 25 nmol/L increased ACAT-1 protein expression level by 2.5-fold, which was completely abolished by anti-U-II antibody, selective UT receptor antagonists (urantide and 4-aminoquinoline), a G-protein inactivator (GDP-␤-S), a c-Src protein tyrosine kinase inhibitor (PP2), a protein kinase C (PKC) inhibitor (rottlerin), a mitogen-activated protein kinase kinase (MEK) inhibitor (PD98059), or a Rho kinase (ROCK) inhibitor (Y27632). Northern blotting analysis indicated that among the 4 ACAT-1 mRNA transcripts (2.8-, 3.6-, 4.3-, and 7.0-kb), the 2.8-and 3.6-kb transcript levels were selectively upregulated by Ϸ1

Our results suggest that increased levels of U-II may play a crucial role in the development of carotid atherosclerosis in hypertensive patients.

Our results provide the first evidence that increased plasma urotensin II level stimulates oxidized low-density lipoprotein and reactive oxygen species production and macrophage foam cell formation via increased expression of CD36, scavenger receptor class A, and acyl-CoA:cholesterol acyltransferase-1, contributing to the development of atherosclerosis in apolipoprotein E-deficient mice. Urotensin II receptor antagonism may be a promising therapeutic strategy against atherosclerosis.

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