This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hasler-Rapacz, J. Articles by Rapacz, J. Search for Related Content PubMed PubMed Citation Articles by Hasler-Rapacz, J. Articles by Rapacz, J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CHOLESTEROL

(Arteriosclerosis, Thrombosis, and Vascular Biology. 1996;16:137-143.)
© 1996 American Heart Association, Inc.

Articles

Effects of Simvastatin on Plasma Lipids and Apolipoproteins in Familial Hypercholesterolemic Swine

Judith Hasler-Rapacz; Herman J. Kempen; Hans M.G. Princen; Bhalchandra J. Kudchodkar; Andras Lacko; Jan Rapacz

From the Department of Genetics and Department of Meat & Animal Sciences, University of Wisconsin, Madison (J.H.-R., J.R.); F. Hoffmann-LaRoche Ltd, Basel, Switzerland (H.J.K.); TNO-PG, The Gaubius Laboratory, Leiden, the Netherlands (H.M.G.P.); and the Department of Biochemistry and Molecular Biology, University of North Texas Health Sciences Center, Fort Worth (B.J.K., A.L.).

Correspondence to Jan Rapacz, PhD, Immunogenetics Laboratory, University of Wisconsin-Madison, 666 Animal Sciences Bldg, 1675 Observatory Dr, Madison, WI 53706-1284. E-mail rapacz@calshp.cals.wisc.edu.

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, C-III, 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 TC250 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 swine 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.

Key Words: swine • simvastatin • animal model • familial hypercholesterolemia • apolipoproteins

This article has been cited by other articles:

				F. S. Czepluch and J. Waltenberger High-dose atorvastatin is associated with impaired myocardial angiogenesis in response to vascular endothelial growth factor in hypercholesterolemic swine: Relevance to the human situation? J. Thorac. Cardiovasc. Surg., June 1, 2007; 133(6): 1685 - 1686. [Full Text] [PDF]

				A. R. Chade, X. Zhu, O. P. Mushin, C. Napoli, A. Lerman, and L. O. Lerman Simvastatin promotes angiogenesis and prevents microvascular remodeling in chronic renal ischemia FASEB J, August 1, 2006; 20(10): 1706 - 1708. [Abstract] [Full Text] [PDF]

				S. H. Wilson, A. R. Chade, A. Feldstein, T. Sawamura, C. Napoli, A. Lerman, and L. O. Lerman Lipid-lowering-independent effects of simvastatin on the kidney in experimental hypercholesterolaemia Nephrol. Dial. Transplant., April 1, 2003; 18(4): 703 - 709. [Abstract] [Full Text] [PDF]

				P. O. Bonetti, S. H. Wilson, M. Rodriguez-Porcel, D. R. Holmes Jr, L. O. Lerman, and A. Lerman Simvastatin preserves myocardial perfusion and coronary microvascular permeability in experimental hypercholesterolemia independent of lipid lowering J. Am. Coll. Cardiol., August 7, 2002; 40(3): 546 - 554. [Abstract] [Full Text] [PDF]

				S. H. Wilson, R. D. Simari, P. J. M. Best, T. E. Peterson, L. O. Lerman, M. Aviram, K. A. Nath, D. R. Holmes Jr, and A. Lerman Simvastatin Preserves Coronary Endothelial Function in Hypercholesterolemia in the Absence of Lipid Lowering Arterioscler. Thromb. Vasc. Biol., January 1, 2001; 21(1): 122 - 128. [Abstract] [Full Text] [PDF]

				J. R. Burnett, L. J. Wilcox, D. E. Telford, S. J. Kleinstiver, P. H. R. Barrett, R. S. Newton, and M. W. Huff Inhibition of HMG-CoA Reductase by Atorvastatin Decreases Both VLDL and LDL Apolipoprotein B Production in Miniature Pigs Arterioscler. Thromb. Vasc. Biol., November 1, 1997; 17(11): 2589 - 2600. [Abstract] [Full Text]