Abstract
Growing human atherosclerotic plaques show a progressive loss of vascular smooth muscle cells (VSMC) becoming soft and vulnerable. Lipid loaded-VSMC show impaired vascular repair function and motility due to changes in cytoskeleton proteins involved in cell-migration. Clinical benefits of statins reducing coronary events have been related to repopulation of vulnerable plaques with VSMC. Here, we investigated whether HMG-CoA reductase inhibition with rosuvastatin can reverse the effects induced by atherogenic concentrations of LDL either in the native (nLDL) form or modified by aggregation (agLDL) on human VSMC motility. Using a model of wound repair, we showed that treatment of human coronary VSMC with rosuvastatin significantly prevented (and reversed) the inhibitory effect of nLDL and agLDL in the repair of the cell depleted areas. In addition, rosuvastatin significantly abolished the agLDL-induced dephosphorylation of myosin regulatory light chain as demonstrated by 2DE-electrophoresis and mass spectrometry. Besides, confocal microscopy showed that rosuvastatin enhances actin-cytoskeleton reorganization during lipid-loaded-VSMC attachment and spreading. The effects of rosuvastatin on actin-cytoskeleton dynamics and cell migration were dependent on ROCK-signalling. Furthermore, rosuvastatin caused a significant increase in RhoA-GTP in the cytosol of VSMC. Taken together, our study demonstrated that inhibition of HMG-CoA reductase restores the migratory capacity and repair function of VSMC that is impaired by native and aggregated LDL. This mechanism may contribute to the stabilization of lipid-rich atherosclerotic plaques afforded by statins.
Highlights
Atherosclerotic lesions with a large lipid-necrotic core and a thin fibrous cap are the most prone to rupture [1] triggering the acute ischemic syndromes
This retention occurs when low density lipoprotein (LDL) bind to the extracellular matrix proteoglycans, as versican [9,10,11] that induces LDL aggregation and leads to dysfunction of the vascular resident cells [12,13]. agLDL upregulate the expression of low-density lipoprotein receptorrelated protein 1 (LRP1) [14,15], which in turn internalizes significant amounts of cholesteryl esters from agLDL contributing to the transformation of vascular smooth muscle cells (VSMC) into lipid loaded cells [15,16,17]
Wound repair kinetics were significantly higher in cells treated with rosuvastatin than in cells incubated with LDL alone (P,0.01 for both nLDL and agLDL)
Summary
Atherosclerotic lesions with a large lipid-necrotic core and a thin fibrous cap are the most prone to rupture [1] triggering the acute ischemic syndromes. A key pathogenic event in the development of atherosclerosis is the retention of colloidal atherogenic lipoproteins, primarily low density lipoprotein (LDL), in the arterial intima This retention occurs when LDL bind to the extracellular matrix proteoglycans, as versican [9,10,11] that induces LDL aggregation (agLDL) and leads to dysfunction of the vascular resident cells [12,13]. In previous studies we have demonstrated that agLDL decrease phosphorylated-MRLC (P-MRLC) levels and impairs migration and wound repair in VSMC [18,19]. These effects could contribute to the development of soft-high risk plaques with decreased VSMC accumulation
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