Esterified Cholesterol Accumulation Induced by Aggregated LDL Uptake in Human Vascular Smooth Muscle Cells Is Reduced by HMG-CoA Reductase Inhibitors

From the Cardiovascular Research Center, CSIC-HSCSP-UAB (V.L.-C., J.M.-G., L.B.); and the Institut de Recerca de l' Hospital de la Santa Creu i Sant Pau (J.M.-G.), Barcelona, Spain.

Correspondence to Prof Lina Badimon, Centro de Investigacion y Desarrollo (CSIC), C/Jordi Girona 18–26, 08034 Barcelona, Spain. E-mail lbmucv{at}cid.csic.es

Abstract—Vascular smooth muscle cell (VSMC) proliferation is a key event in the development of atherosclerotic lesions. VSMCs synthesize extracellular matrix, where low density lipoproteins (LDLs) are trapped and become aggregated (agLDL). The objective of this study was to investigate the cholesterol uptake and accumulation triggered by agLDL in comparison with native LDL (nLDL) on unstimulated and platelet-derived growth factor–stimulated human aortic VSMCs and the role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors on these processes. Esterified cholesterol (EC) accumulation induced by agLDL in VSMCs was correlated with the degree of aggregation and concentration. The EC content of VSMCs treated with 100 µg/mL of agLDL (80% aggregated) increased 70-fold over that in VSMCs incubated with the same concentration of nLDL. Whereas nLDL-derived EC was increased approximately twofold in platelet-derived growth factor–stimulated VSMCs, there was no effect of platelet-derived growth factor (10^-9 mol/L) on the uptake of agLDL. The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin (5 µmol/L) reduced EC accumulation derived from agLDL uptake by 58% and 35% in platelet-derived growth factor—stimulated and unstimulated VSMCs, respectively. This inhibition was overcome by geranylgeraniol (10 µmol/L) and partially by farnesol (10 µmol/L). Fluorescence microscopy of the cellular internalization of agLDL labeled with the fluorochrome 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine demonstrated that simvastatin reduces EC accumulation derived from agLDL by inhibiting its endocytosis and that the effect is completely reversed by geranygeraniol. These results indicate that agLDLs are rapidly internalized by human VSMCs and that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors modulate EC accumulation. These data suggest a possible mechanism by which statins could contribute to the passivation and stabilization of actively growing atherosclerotic lesions.

Key Words: LDL aggregation • vascular smooth muscle cells • HMG-CoA reductase inhibitors

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