Roles of Vasoactive Agents in Macrophage Foam Cell Formation and Atherosclerosis

Abstract

Hypertension is a well-known risk factor for atherosclerosis, and vasoactive agents play a key role as a mediator between the two diseases. This study explored the role of human urotensin II (UII), the most potent vasoconstrictor to date, in atherosclerotic plaque formation in hypertensive patients, and the effects of UII and other vasoactive agents on foam cell formation and acyl-CoA:cholesterol acytransferase-1 (ACAT1) expression in human monocyte-macrophages. Plasma UII levels were significantly higher in 50 patients with essential hypertension than in 31 normotensive controls (7.9 vs. 2.3 ng/ml), and correlated positively with systolic blood pressure, carotid artery intima-media thickness, and plaque score. In primary cultured human monocyte-macrophages, UII enhanced acetylated LDL-induced cholesteryl ester accumulation along with an increase in ACAT1 protein expression by ∼2.5-fold. ACAT activity and ACAT1 mRNA levels were also increased. The ACAT1 expression increased by UII was completely abolished by UII receptor (UT) antagonists and inhibitors of G protein, c-Src tyrosine kinase, protein kinase C (PKC), extracellular signal-regulated kinase (ERK), and Rho kinase. UII stimulated ACAT1 expression at the highest level among vasoactive G-protein agonists such as endothelin-1, angiotensin II, serotonin, and salusin-β. These results suggest that UII accelerates foam cell formation by upregulating ACAT1 expression via UT/G protein/c-Src/PKC/ERK and Rho kinase pathways in human monocyte-macrophages, leading to the development of atherosclerotic plaque in essential hypertension.