Abnormal effects of hypertriacylglycerolemic very low-density lipoproteins on 3-hydroxy-3-methylglutaryl-CoA reductase activity and viability of cultured bovine aortic endothelial cells

Our previous studies showed that hypertriacylglycerolemic very low-density lipoproteins (VLDL) are functionally abnormal. Hypertriacylglycerolemic VLDL, but not normal VLDL, suppress 3-hydroxy-3-methylglutaryl-CoA reductase in fibroblasts cultured from normal human subjects. To determine if hypertriacylglycerolemic VLDL also differ from normal VLDL in their interaction with vascular cells, their effects on the activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase in cultured subconfluent bovine endothelial cells were quantified. All hypertriacylglycerolemic VLDL subclasses (S_f 100-400, S_f 60-100 and S_f 20-60) from a Type III hyperlipoproteinemic subject were even more effective than normal low-density lipoproteins (d 1.006-1.063) (LDL) in suppression; 50 and 100% suppression by S_f 100-400 hypertriacylglycerolemic VLDL occurred at 0.5 and 5 μg protein/ml, respectively. The VLDL subclasses from two subjects with Type V hyperlipoproteinemia were comparable to LDL in suppression. By contrast, under experimental conditions when normal LDL gave 50% suppression at 1-5 μg protein/ml, neither normal S_f 100-400 VLDL nor high-density lipoproteins (HDL) (d 1.063-1.21) suppressed, even at lipoprotein concentrations of 35 and 200 μg protein/ml, respectively. The smaller S_f 20-60 VLDL subclass from normal plasma suppressed, but with less than 20% of the potency of LDL. LDL and hypertriacylglycerolemic VLDL also suppressed the activity of 3-hydroxy-3-methyl-glutaryl-CoA reductase in confluent endothelial cell cultures. Moreover, exposure to low levels of hypertriacylglycerolemic VLDL, but not normal VLDL or LDL, reduced the number of viable endothelial cells up to 2-fold. We suggest that cytotoxic effects of hypertriacylglycerolemic VLDL on endothelial cells could impair the normal function of the endothelium in vivo.