Survival and cardiovascular pathology of heterozygous Watanabe heritable hyperlipidaemic rabbits treated with pravastatin and probucol on a low-cholesterol (0.03%)-enriched diet

Abstract

This study was aimed at determining the effects of a combined pravastatin and probucol regimen on survival and vascular pathology of heterozygous Watanabe heritable hyperlipidaemic (WHHL) rabbits fed a low-cholesterol (0.03%)-enriched diet. Pravastatin monotherapy preceded the combined treatment. In animals receiving pravastatin and the enriched diet (verum group; n = 6), mean total serum cholesterol levels were consistently lowered at a dosage of 5 mg/kg pravastatin and with the combined treatment. Survival was increased (median 45 vs 25 months), while coronary atherosclerosis was less obstructive and altered to a more fibrous type than in controls (n = 8). The extent of aortic lesions, as determined by the relative plaque volume, was not related to survival in either group. However, aortic plaque types in verum group animals revealed less severe stages with a different composition and architecture, with a lower relative content of macrophage-derived foam cells and necrosis and a higher relative content of extracellular matrix. There was also a thicker fibrous cap than in control animals of similar age. Our data reveal a beneficial effect on survival of heterozygous WHHL rabbits when lipid-lowering and antioxidative treatment are combined. This appears to be due both to reduced coronary atherosclerosis and to a different, more stable type of atherosclerotic disease in this animal model.

Processes Involved in the Site-Specific Effect of Probucol on Atherosclerosis in Apolipoprotein E Gene Knockout Mice

“…Given its preponderance, this increase in collagen can explain why probucol, overall, increased lesion size at the sinus. Our findings are consistent with previous reports on compositional changes caused by probucol in coronary arteries of hypercholesterolemic rabbits 14,15 and nonhuman primates. 13 Total cell numbers, the percentages of lesion comprised of macrophages (M) and extracellular matrix (ECM), and mRNA for F4/80 antigen were determined as described in the Methods section.…”

“…Importantly, these changes are associated with a more stable plaque type, less vulnerable to rupture, and in the rabbit have been reported to increase survival. 15 Therefore, the action of probucol at the aortic sinus in apoE Ϫ/Ϫ , and possibly also LDL receptor Ϫ/Ϫ , 31 mice may be considered beneficial rather than pro-atherogenic.…”

“…Importantly, these changes are associated with a more stable plaque type, less vulnerable to rupture, and in the rabbit have been reported to increase survival. 15 Therefore, the action of probucol at the aortic sinus in apoE Ϫ/Ϫ , and possibly also LDL receptor Ϫ/Ϫ , 31 mice may be considered beneficial rather than pro-atherogenic.A striking feature is that in the descending aorta, probucol almost completely prevented atherosclerosis to an extent exceeding that reported for most other interventions. As discussed, this could not be explained by inhibition of lipid or lipoprotein lipid oxidation.…”

“…12 In animal models of atherosclerosis, probucol alters the cellular composition and proliferation, 13,14 and inhibits coronary heart disease and death. 15,16 It also prevents intimal thickening after balloon injury independent of cholesterol-lowering and inhibition of lipoprotein lipid oxidation, and instead promotes functional re-endothelialization and inhibits vascular smooth muscle cell proliferation via induction of heme oxygenase-1. 17,18 Strikingly, in apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mice, probucol increases lesion size at the aortic sinus 19 while at the same time it strongly inhibits atherosclerosis in the descending aorta.…”

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.…”