Effects of pravastatin on cholesterol metabolism of cholesterol‐fed heterozygous WHHL rabbits

Abstract

1 We administered the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin at a daily dose of 1 mg kg 71 body weight to cholesterol-fed (0.03%) heterozygous Watanabe heritable hyperlipidaemic rabbits, an animal model for heterozygous familial hypercholesterolaemia. 2 After 12 months of cholesterol treatment, immunohistochemistry with the monoclonal antibody 9D9 was used to detect hepatic low density lipoprotein (LDL) receptors, which were quanti®ed by densitometry. In addition we determined LDL receptor mRNA by competitive reverse transcriptase polymerase chain reaction. The cholesterol precursor lathosterol and the plant sterol campesterol were analysed by gas-liquid chromatography. 3 The drug reduced total plasma cholesterol levels by 51% (P=0.04), when compared to the control group. Unexpectedly, hepatic LDL receptor density and mRNA showed no signi®cant dierences between the groups. Total plasma levels of lathosterol and campesterol also revealed no signi®cant dierences between the groups, if expressed relative to plasma cholesterol. 4 The ®ndings suggest that mechanisms other than induced hepatic LDL receptors are responsible for the cholesterol-lowering eect of pravastatin in this animal model. We propose a reduced cholesterol absorption eciency compatible with similar campesterol levels between both groups observed in our study.

Recommendation on Design, Execution, and Reporting of Animal Atherosclerosis Studies: A Scientific Statement From the American Heart Association

“…61 In addition to these 2 models, a substrain of WHHL was created for examination of robust coronary atherosclerosis. 62 There are also several rabbit transgenic models that modify atherosclerosis, including apoE deficiency. 63 Overall, rabbits can be cost equivalent to mice at purchase, although they are more expensive to house and feed.…”

Low-Dose Cerivastatin Inhibits Spontaneous Atherogenesis in Heterozygous Watanabe Hyper lipidemic Rabbits

“…It is worth noting that in previous studies heterozygous WHHL rabbits showed spontaneous atherosclerotic lesions [10]which were not observed until at least 2 years of age [11]. In heterozygous WHHL from another breeding, serum cholesterol levels in the range of those from control NZW fed a standard diet were found so that a 0.03% cholesterol-enriched diet was needed to facilitate lesion development [12, 13]. We can speculate that, due to spontaneous selection, there is a more or less remarkable deficit in the hepatic LDL receptor in inbred animals which in turn makes heterozygous WHHL rabbits more or less prone to developing early lesions.…”