Similar to human familial hypercholesterolemia, WHHL rabbits have a genetically reduced LDL receptor function, resulting in 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). The defect is caused by a deletion of 12 nucleotides from the LDL receptor gene, resulting in a deletion of four amino acids in the cysteine-rich LDL-binding domain of the LDL receptor protein (Science 1986; 232: 1230-1237). A recent study reported deletion of 11 base pairs (Sci Rep 2016 Jun 1;6:26942). In the LDL receptor protein synthesized from this mutant gene, the precursor is synthesized normally, but maturation of the LDL receptor protein is delayed and it is not transported to the cell surface at the normal rate (Mol Biol Med 1983; 1: 353-367).

        In WHHLMI rabbits, the plasma cholesterol level averages about 1,100 mg/dl before 6 months of age, about 900 mg/dl at 12 months of age, and about 800 mg/dl at 18 months of age. Plasma triglyceride levels are 150-300 mg/dl. About 70% of cholesterol is distributed in the LDL fraction, with only a few percent in the HDL fraction.

        In experiments using liver perfusate, it was observed that the accumulation rate of apoB-100 was no different between normal and WHHL rabbits, and that little or no apoB-48 accumulated in the VLDL fraction (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). Inhibition of hepatic microsomal triglyceride transfer protein (MTP) activity reduced VLDL secretion and lowered plasma LDL concentrations in homozygous WHHL rabbits, suggesting that MTP inhibitors have lipid-lowering effects in homozygous familial hypercholesterolemia (Eur J Pharmacol 2001; 431: 127-131 ).

        Plasma CETP (cholesteryl ester transfer protein) activity in WHHL rabbits is approximately 2-3 times higher than that in normal rabbits (Arteriosclerosis 1986; 6:345-351). High CETP activity in WHHL rabbits may be the reason for low HDL cholesterol.
Although LPL activity in WHHL rabbits is similar to that in heterozygous WHHL rabbits, HTGL activity is about two times higher than in heterozygotes (Biochem J 1990; 272: 647-651). Compared with normal rabbits, WHHMI rabbits have approximately 1.5-fold higher LPL and approximately 5-fold higher HTGL. Unlike mice, rabbits have low HTGL activity in plasma before heparin administration, similar to that of humans (Exp Anim 2019;68:267-275).

        A kinetic study of ¹²⁵I-labeled chylomicrons showed the fractional catabolic rate in WHHL rabbits was similar to that of normal rabbits (Proc Natl Acad Sci USA 1982; 79: 3623-3627). On the other hand, it has been reported that the catabolism of chylomicrons is delayed in WHHL rabbits, and that this is due to an abnormality in the LDL receptor (J Biol Chem 1995; 270(15): 8578-8587).

        It has been reported that, compared with normal rabbits, the fractional catabolic rate of HDL apoA-I in WHHL rabbits is 1.7 times higher, and the synthesis rate is reduced to approximately 50% (Atherosclerosis 1989; 79: 225-230). This may also be related to the fact that CETP activity in plasma is two to three times higher than in normal rabbits (Arteriosclerosis 1986; 6:345-351).

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

        In current WHHLMI rabbits, aortic atherosclerosis is observed from 2 months of age, despite being fed a normal standard rabbit diet. Lesions first occur at the openings of the arterial branches. At 6 months of age, aortic lesions extend to approximately 40% of the aortic surface (arch, thoracic, and upper abdominal areas). At 12 months of age, lesions extend to the abdominal aorta, covering approximately 70% of the aortic surface. Beyond 18 months of age, aortic lesions cover most of the aorta.
      Regarding the lesional composition (Arterioscler Thromb 1994; 14: 931-937; J Atheroscler Thromb 1994; 1: 45-52), early lesions have many macrophages in the intima and few smooth muscle cells, with some macrophages infiltrating the arterial media. In transitional lesions observed at around 12 months of age, there is an increase in large foamy cells derived from macrophages deep in the intima, and the surface is covered with a fibromuscular cap. After 18 months of age, the cellular components decrease, but collagen fibers, extracellular lipid accumulation, and cholesterol creft increase. In some cases, calcium accumulation is observed in these advanced lesions.

Occurence of coronary lesions
      The mutant rabbits from which the WHHL rabbits were derived had severe atherosclerotic lesions in the coronary arteries. However, during the development of the WHHL rabbit line, the mutant rabbits were crossed with normal rabbits (JW rabbits), and when the line was established, the incidence of coronary lesions was very low. As a result of selective breeding (see "Development of the WHHL rabbit line"), coronary lesions were observed from 2 months of age, even when fed a standard diet. Lesions occur mainly in the left main coronary trunk, the origin of the right coronary artery, and the left circumflex artery. In rabbits, the left circumflex artery is thicker and longer than the left anterior descending artery (J Ateroscler Thromb 2018; 25:393-404). In WHHLMI rabbits, the average percent coronary stenosis of the circumflex artery (percentage of plaque area in the area surrounding the internal elastic lamina) is approximately 50% at 6 months of age, approximately 70% at 12 months of age, and approximately 80% at 18 months of age or older (Exp Anim 2004;53:339-346).

Components of coronary lesions
      The lesion composition of coronary plaques in WHHLMI rabbits is relatively fibromuscular compared to aortic lesions (Arterioscler Thromb 1994; 14: 931-937, Exp Anim 2004;53:339-346). However, several WHHLMI rabbits show macrophage-rich coronary plaques.
Many WHHLMI rabbits have vulnerable plaques (lesions consisting of large lipid core covered by a thin fibrous cap) in the coronary arteries that lead to acute myocardial infarction.

Coronary response to serotonin
      Coronary arteries with atherosclerotic lesions exhibited the enhanced contraction and Ca²⁺ mobilization in response to serotonin. The 5-HT_1B receptor, which is upregulated by atherosclerosis, are thought to mediate the enhancing effects of serotonin (Circulation 2001; 103: 1289-1295).

Outward remodeling of coronary arteries
Coronary arteries with atherosclerotic lesions show outward remodeling, and WHHLMI rabbits, which are prone to coronary atherosclerosis, are useful animals for studying coronary outward remodeling. We have demonstrated new insights into the preservation of the coronary lumen during the progression of coronary atherosclerosis (Coronary Artery Disease 2004 Nov; 15(7): 419-426);

Correlation between coronary artery running pattern and severity of coronary lesions
     Even if serum cholesterol levels are the same, there are large individual differences in the progression of coronary artery disease. It has been suggested that these individual differences may be related to the courserunning pattern of the coronary arteries. The more curvature there is in the coronary artery, the more advanced the coronary artery stenosis is（J Atheroscler Thromb 2018;25:393-404).

Serum markers for coronary lesions
Metabolomic analysis using WHHLMI rabbits identified serum markers specific to coronary artery lesions (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 of hypercholesterolemia and coronay atherosclerosis

    1. Hypercholesterolemia


    2. Coronary atherosclerosis



VII. Acute Coronary Syndromes
      In human coronary arteries, there are atherosclerotic lesions consisting of a partially thinned fibrous cap covering a large lipid core (vulnerable plaque), and it is believed that rupture of these lesions can lead to sudden cardiac death. Such unstable lesions were also observed in the coronary arteries of WHHLMI rabbits, but no ruptured coronary plaques were observed under normal conditions. Therefore, we hypothesized that a secondary factor is required for rupture of unstable coronary plaques and examined whether unstable coronary plaque would rupture by inducing coronary vasospasm.(Arterioscler Thromb Vasc Biol. 2013 Nov; 33(11): 2518-2523).
      When WHHLMI rabbits were given a bolus of ergonovine intravenously while receiving a continuous infusion of norepinephrine, ST elevation and ST depression were observed on the electrocardiogram, and these changes were normalized by administration of nitroglycerin. Coronary angiography showed a decrease in coronary blood flow with ergonovine administration and a restoration of coronary blood flow with nitroglycerin administration. These changes indicate the development of coronary artery spasm. Echocardiography showed that systolic ventricular diameter was enlarged after the onset of coronary artery spasm, resulting in cardiac systolic dysfunction. Serum myocardial ischemia markers (H-FABP, c-troponin I, and myoglobin) were elevated 4 hours after the onset of coronary artery spasm.
      In pathological examination of coronary plaques, eruptions of macrophages into the lumen from endothelial clefts were observed, and in a few cases, thrombus formation accompanied by rupture of coronary plaques was also observed.



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）
The lipoprotein metabolism and arterial lesions in rabbits are similar to those in humans, but in mice they are significantly different from those in humans. The characteristics of rats are similar to those of 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