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Effects of simvastatin on plasma lipids and apolipoproteins in familial hypercholesterolemic swine

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Author: Hasler-Rapacz, J. · Kempen, H.J. · Princen, H.M.G. · Kudchodkar, B.J. · Lacko, A. · Rapacz, J.
Type:article
Date:1996
Institution: Gaubius Instituut TNO
Source:Arteriosclerosis, Thrombosis, and Vascular Biology, 1, 16, 137-143
Identifier: 233194
Keywords: Biology · animal model · apolipoproteins · familial hypercholesterolemia · simvastatin · swine · apolipoprotein a · apolipoprotein b · apolipoprotein c3 · apolipoprotein e · high density lipoprotein cholesterol · hydroxymethylglutaryl coenzyme a reductase · lathosterol · lipid · low density lipoprotein cholesterol · phosphatidylcholine sterol acyltransferase · simvastatin · triacylglycerol · very low density lipoprotein cholesterol · animal experiment · animal model · animal tissue · article · calculation · cholesterol blood level · dose response · enzyme activity · hypercholesterolemia · hyperlipidemia · lipid analysis · lipid blood level · lipoprotein blood level · nonhuman · priority journal · statistical analysis · swine · Animals · Apolipoprotein A-I · Apolipoprotein C-III · Apolipoproteins · Apolipoproteins B · Apolipoproteins C · Apolipoproteins E · Cholesterol · Cholesterol, HDL · Cholesterol, LDL · Enzyme Inhibitors · Female · Hydroxymethylglutaryl-CoA Reductase Inhibitors · Hyperlipoproteinemia Type II · Lipids · Male · Swine · Swine Diseases · Triglycerides

Abstract

Familial hypercholesterolemia (FHC) in swine, which resembles human familial combined hyperlipidemia, is a complex lipid and lipoprotein disorder associated with the development of severe coronary lesions similar to those occurring in advanced human coronary disease. The disorder is characterized by elevated plasma total cholesterol (TC), triglycerides (TG). LDL-cholesterol (LDL- C), apolipoproteins (apo) B, CIII, and E, and by decreased levels of HDL-cholesterol (HDL-C), apoA-I, and lecithin:cholesterol acyltransferase (LCAT) activity. A dose-response study with simvastatin, a specific inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, was conducted in four treatment groups of FHC animals exhibiting TC≥250 mg/dL. The animals were fed 0, 80, 200, or 400 mg simvastatin daily for 3 weeks. The measured serum parameters included the levels of TC, VLDL-C, LDL- C, HDL-C, TG, lathosterol, apoA-I, B, C-III, and E, as well as LCAT activity. Simvastatin at 200 mg/d significantly decreased the levels of TC (-25%). LDL-C (-27%), lathosterol (-40%), apoB (- 22%), apoC-III (-37%), and apoE (-24%) and modestly decreased the levels of HDL-C (-12%) and apoA-I (-11%) (percent relative to the average pretreatment and posttreatment baseline values) but did not affect the levels of TG, VLDL-C, the lathosterol/TC ratio, or LCAT activity. The levels of TC, LDL-C, apoB, and E were also lowered by simvastatin at 80 or 400 mg/d, but to a lesser extent than at 200 mg/d, while the other parameters were not influenced at these doses. The simvastatin-induced decreases of LDL-C, HDL-C, and apoa- I, B, C-III, and E were significantly correlated among each other. These results show that the trend of responses in TC. LDL-C, apoB, apoC-III, and apoE to simvastatin in the FHC swines is similar to that observed in humans, although the drug is less potent and efficacious in swine, while the results are different from those in humans with regard to the remaining parameters. Chemicals/CAS: Apolipoprotein A-I; Apolipoprotein C-III; Apolipoproteins B; Apolipoproteins C; Apolipoproteins E; Apolipoproteins; Cholesterol, 57-88-5; Cholesterol, HDL; Cholesterol, LDL; Enzyme Inhibitors; Hydroxymethylglutaryl-CoA Reductase Inhibitors; lathosterol, 80-99-9; Lipids; Triglycerides