Opposite pattern of MDR1 and caveolin-1 gene expression in human atherosclerotic lesions and proliferating human smooth muscle cells

Cholesterol esterification and smooth muscle cell (SMC) proliferation are t he crucial events in the development of atherosclerotic lesions. The object ive of this study was to analyse cholesterol esterification and the express ion of MDR1 (multidrug resistance), ACAT (acyl-CoA:cholesterol acyltransfer ase) and caveolin-1 genes in atherosclerotic and healthy vascular walls, in SMCs obtained from atherosclerotic lesions and saphenous veins. Results de monstrated higher levels of cholesterol esters, ACAT and MDR1 mRNAs and low er levels of caveolin-1 mRNA in atherosclerotic segments compared to adjace nt serial sections of the same artery and the corresponding non-atheroscler otic arteries from cadaveric donors. SMCs isolated from atherosclerotic pla ques manifested an increased capacity to esterify cholesterol and to grow a t a faster rate than SMCs isolated from saphenous veins. In addition, when SMCs from atherosclerotic plaques were cultured in the presence of progeste rone, a potent inhibitor of cholesterol esterification, significant growth suppression was observed. Am increase in ACAT and MDR1 expression and a con comitant decrease in caveolin-1 expression were also observed in SMCs isola ted from atherosclerotic arteries as early as 12 h after serum stimulation. An opposite pattern was found when SMCs were treated with progesterone. Th ese findings support the idea that cholesterol esterification plays a role both in early atherogenesis and in clinical progression of advanced lesions and raise the possibility that the cholesterol ester pathway might directl y modulate the proliferation of SMCs.