Similar to human Familial Hypercholesterolemia, LDL receptor function is genetically reduced in WHHL rabbits and they show hypercholesterolemia (FEBS Lett 1980; 118: 81-84; Eur J Biochem 1981; 118: 557-564; Proc Natl Acad Sci USA 1981; 78: 2268-2272; J Biol Chem 1981; 256: 9789-9792). This defect arises from an in-frame deletion of 12 nucleotides that eliminates four amino acids from the cysteine-rich ligand binding domains of the LDL receptor (Science 1986; 232: 1230-1237). A recent study reported deletion of 11 base pairs (Sci Rep 2016 Jun 1;6:26942). From this mutant gene, although the precursor of LDL receptor proteins are synthesized normally, the maturation of the LDL receptor protein is delayed and is not transported to the cell surface at a normal rate (Mol Biol Med 1983; 1: 353-367).

        In our present WHHL rabbits, the average plasma cholesterol levels are about 1,100 mg/dl when they are below 6 months old, about 900 mg/dl at 12 months old, and about 800 mg/dl at 18 months old. The average plasma triglyceride levels are between 150 and 300 mg/dl. About 70% of the cholesterol is distributed in LDL fractions, and only a few % in HDL fractions.

        The rate of accumulation of apoB-100 does not differ in perfusates of liver from normal and WHHL rabbits and little or no apoB-48 is accumulated in VLDL fractions (Proc Natl Acad Sci USA 1983; 80: 6096-6100). ApoB-containing lipoproteins other than VLDL are not secreted from the liver of WHHL rabbits (Proc Natl Acad Sci USA 1983; 80: 6096-6100). An inhibition of the hepatic microsomal triglyceride transfer protein (MTP) activity diminished the VLDL secretion and reduced the plasma LDL levels in homozygous WHHL rabbits. This suggests that MTP inhibitors should have lipid-loweringeffects against homozygous familial hypercholesterolemia. (Eur J Pharmacol 2001; 431: 127-131 ).

        The plasma CETP activity of WHHL rabbits is about 2 to 3 times higher than that of normal rabbits (Arteriosclerosis 1986; 6:345-351). High CETP activity in WHHL rabbits may be the reason for low HDL cholesterol.
Although the LPL activity of WHHL rabbits is similar to heterozygous WHHL rabbits, the HTGL activity is about 2 times higher than that of the heterozygotes (Biochem J 1990; 272: 647-651). Compared to normal rabbits, in WHHMI rabbits, LPL is about 1.5 times higher and HTGL is about 5 times higher.In rabbits, unlike mice, there is little HTGL activity in plasma before administration of heparin and it is similar to humans.(Exp Anim 2019;68:267-275)

        In a kinetic study of ¹²⁵I-labeled chylomicrons, the fractional catabolic rate in WHHL rabbits was similar to normal rabbits (Proc Natl Acad Sci USA 1982; 79: 3623-3627).On the other hand, in WHHL rabbits, catabolism of chylomicron is delayed, and there are reports that abnormality of LDL receptor is involved as a cause (J Biol Chem 1995; 270(15): 8578-8587).

        Compared to normal rabbits, the fractional catabolic rate of HDL apoA-I in WHHL rabbits is as high as 1.7 times, and the synthetic rate is reported to be reduced to about 50% (Atherosclerosis 1989; 79: 225-230). It may also be related to the fact that CETP activity in blood is as high as 2-3 times that of normal rabbits(Arteriosclerosis 1986; 6:345-351).

        The plasma cholesterol levels of WHHL rabbits are gradually decreased with age (Metabolism 2000; 49: 552-556). The HMG-CoA reductase activity of the liver microsomal fraction is increased above 12 month-old. The ACAT activity is decreased between 2 month-old and 6 month-old and remains constant thereafter. The activity of cholesterol-7a hydroxylase is almost constant. The cholesterol contents in the whole liver and the microsome fraction are constant. The VLDL secretion rate is decreased with age.

        In current WHHLMI rabbits aortic atherosclerosis is observed from 2 months old despite usual standard rabbit feeding. The lesions develop first at the orifices of arterial branches. At 6 month-old, aortic lesions expanded to about 40% of the aortic surface. At 12 month-old, the lesions cover about 70% of the aortic surface. Above 18 month-old, the aortic lesions cover most of the aorta.
      Regarding lesional composition (Arterioscler Thromb 1994; 14: 931-937; J Atheroscler Thromb 1994; 1: 45-52), in early lesions, many macrophages and few SMCs are observed in the intima and some macrophages penetrate into the arterial media.       In transitional lesions observed at about 12 months old, large foam cells derived from macrophages, are increased in the deep area of the intima, and a fibromuscular cap covers the surface. Above 18 months old, cellular components are decreased, but collagen fibers, extracellular lipid accumulation, and cholesterol cleft are increased. In some case, calcium accumulation is also observed in these advanced lesions.

Occurence of coronary lesions
      A severe arteriosclerotic lesion was observed in the coronary artery in a mutant rabbit that was the origin of the WHHL rabbit, but as a result of mating with a normal rabbit (JW rabbit) during the development of WHHL rabbit strain, incidence of coronary artery lesions at that time established as a lineage was low rate. After the results of selective breeding(see the section of "Development of the WHHL rabbit strain"), coronary lesions were observed from 2 months old even with feeding of standard chow. The lesions develop mainly at the main stem of the left coronary artery, the origin of the right coronary artery, and the left circumflex arteries. In rabbits, the left circumflex artery is larger and longer than the left anterior descending artery (J Ateroscler Thromb 2018; 25:393-404). In WHHLMI rabbits, the average coronary narrowing (% of plaque area in the area surrounding the internal elastic lamina) of the circumflex artery is about 50% at 6 months old, about 70% at 12 months old, and about 80% above 18 months old(Exp Anim 2004;53:339-346).

Components of coronary lesions
      Lesional composition of coronary plaques is relatively fibromuscular compared with the aortic lesions (Arterioscler Thromb 1994; 14: 931-937;   Exp Anim 2004;53:339-346). However, several WHHL rabbits show macrophage-rich coronary plaques.
      Atherosclerotic coronary arteries exhibited the enhancement in contraction and Ca²⁺ mobilization in response to serotonin. The 5-HT_1B receptor, which is upregulated by atherosclerosis, most likely mediates the augmenting effects of serotonin. (Circulation 2001; 103: 1289-1295)

Outward remodeling of coronary arteries
Atherosclerotic coronary arteries show outward remodeling and coronary atherosclerosis-prone WHHL rabbits are useful animal for studies about coronary outward remodeling. We demonstarted the novel insights into coronary lumen preservation during progression of coronary atherosclerosis (Coronary Artery Disease 2004 Nov; 15(7): 419-426);

Correlation between coronary artery running pattern and severity of coronary lesions
     Progression of coronary artery lesion has individual differences. It is suggested that the individual difference is related to the running pattern of coronary arteryies（J Atheroscler Thromb 2018;25:393-404).

Serum markers for coronary lesions
Serum markers specific for coronary artery lesions were identified in a study using WHHLMI rabbits.(Atherosclerosis 2019;284:18-23).


    3). Cerebral artery lesions


    4). Other arterial lesions



IV. The characteristics of WHHLMI rabbit
(Arterioscler Thromb Vasc Biol 2003;23 (7): 1239-1244); Commentary to the International Atherosclerosis Society, IAS Website (http://www.athero.org/comm-index.asp) September 5, 2003.; Exp Anim 2004; 53 (4): 339-346; J Atheroscler Thromb 2004 Sep; 11 (4): 184-189)




V. Other property




VI. Inheritance mode

    1. Hypercholesterolemia


    2. Coronary atherosclerosis



VII. Acute Coronary Syndromes
      In humans, it is thought that coronary pulaques are prone to rupture as a part of the fibrous capsule covering the large lipid core is thinned, and these plaques are said to be an unstable plaque leading to sudden cardiac death. In WHHLMI rabbits, such unstable lesions were observed in the coronary arteries, but ruptured coronary plaques could not be found.Therefore, we thought that secondary factors are necessary to cause unstable coronary lesions to rupture, and attempted to induce rupture of coronary lesions by evoking coronary spasm (Arterioscler Thromb Vasc Biol. 2013 Nov; 33(11): 2518-2523).
      When bolus intravenous injection of ergonovine under continuous infusion of norepinephrine, ST elevation and ST decline are observed in the electrocardiogram, and these changes are normalized by administration of nitroglycerin. Reduction and recovery of coronary blood flow can be confirmed by coronary angiography. These changes inidicate the occurrence of coronary spasm. In echocardiography, the systolic ventricular diameter increases when spasm occurs, causing heart contraction failure. Serum myocardial ischemic markers (H-FABP, cTroponin-I, Myoglobin) increase 4 hours after the occurrence of spasm.
      In coronary lesions, the eruption of macrophages from the clefts of the endothelial cells into the lumen was observed, and the formation of thrombus accompanied by the rupture of the coronary lesion was observed although it was a small number.



VIII. Other abnormal findings



IX. Species difference (Comparison with transgenic or KO mice)
Please see the table summarizing species differences:  Essence of species difference about lipoprotein metabolism, atherosclerosis, and myocardial characteristics（PDF）
Lipoprotein metabolism and arterial lesions in rabbits are similar to thaose of a humans, but mice differ significantly from humans. Characteristics of rats are similar to mice.

    1) Lipid metabolism

    2) Atherosclerosis

    3) Myocardial characteristics



X. Studies using WHHL rabbits or WHHLMI rabbits

Outline of WHHL rabbits

Homepage of WHHL and WHHLMI rabbit