The role of hypertriglyceridemia in the development of atherosclerosis and endothelial dysfunction

Abstract

A hereditary postprandial hypertriglyceridemic rabbit (PHT rabbit) is a new dyslipidemic model showing remarkably high plasma triglycerides with only limited elevation of plasma total cholesterol. In PHT rabbits, plasma triglyceride was markedly elevated postprandially compared with healthy Japanese white (JW) rabbits. In physiological experiments, the ring preparation of the thoracic aorta was suspended in an organ bath filled with modified Krebs-Henseleit solution, and the developed tension was recorded. Endothelial function was evaluated by acetylcholine-induced vasorelaxation in each preparation with intact endothelium. The acetylcholine-induced endothelium-dependent relaxation was diminished in PHT compared with JW rabbits, suggesting endothelial dysfunction in PHT rabbits. Histological examination was carried out in adipose tissue, liver and aorta. They were fixed in formaldehyde and embedded in paraffin. The tissues were sliced (4 μm) and stained using hematoxylin-eosin solution. In the adipose tissue, the visceral fat accumulated, and the size of adipose cells was enlarged in PHT rabbits. The liver of the PHT rabbit was fatty and degenerated. In aorta, increased intimal thickness was observed, suggesting the progression of atherosclerosis in the PHT rabbit. This study suggests the important role of postprandial hypertriglyceridemia in atherosclerosis. By using PHT rabbits, the effects of hypertriglyceridemia on health and diseases could be evaluated precisely.

Figure 1

The method of measuring the response of vascular relaxation by acetylcholine in phenylephrine-precontracted aorta. Each preparation was precontracted with phenylephrine (1 μM) to reach maximal tension, then acetylcholine was added cumulatively to measure the relaxation response. In some experiments, the endothelium of the ring preparation was mechanically denuded to show the endothelium-dependent response.

Figure 2

Plasma lipid concentrations in the normal JW rabbit before (preprandial; blue columns) and 18 h after feeding (postprandial; red columns). (a) Triglyceride (TG) (b) Total cholesterol (TC).

Figure 3

Plasma lipid concentrations in young and adult 33-months-old PHT rabbits before (preprandial; blue columns) and 18 h after feeding (postprandial; red columns). (a) Triglyceride (TG); (b) Total cholesterol (TC). Number of animals in parentheses.

Figure 4

Effect of hypertriglyceridemia on the size of adipose cells. Histological examination of adipose cells (a–d) and size of adipose cells (e); Each tissue was fixed in formaldehyde and embedded in paraffin. They were sliced (4 μm) and stained with hematoxylin-eosin solution. (a) 12-month-old JW rabbit; (b) 35-month-old JW rabbit; (c) 12-month-old PHT rabbit; (d) 33-month-old PHT rabbit.

Figure 5

Liver of the normal JW rabbit. (a) and (b): 12-month-old JW rabbits. (c) and (d): 35-month-old JW rabbits. (b) and (d) are enlarged pictures of (a) and (c), respectively.

Figure 6

Lipid accumulation in PHT rabbit liver. (a) and (b): 12-month old PHT rabbits. (c) and (d): 33-month-old PHT rabbits. (b) and (d) are enlarged pictures of (a) and (c), respectively.

Figure 7

Aorta of the normal JW rabbit. (a,b) aorta from 12-month-old JW rabbit; (c,d) aorta from 35-month-old JW rabbit. E: endothelium, S: smooth muscle, A: adventitia, (b) and (d) are enlarged pictures of (a) and (c), respectively.

Figure 8

Atherosclerotic changes in PHT aorta. (a,b) aorta from 12-month-old PHT rabbit; (c,d) aorta from 33-month-old PHT rabbit. E: endothelium, S: smooth muscle, A: adventitia, * indicates atherosclerotic intimal thickening. (b) and (d) are enlarged pictures of (a) and (c), respectively.

Figure 9

Age-related changes in the acetylcholine-induced endothelium-dependent relaxation of PHT aorta. The acetylcholine-induced relaxation in normal Japanese white rabbits is shown by the green line.