Analysis of Genetic Factors of Atherogenesis (1980)

Since typical rapid arterial fat deposition was first noted in hypertensive rats (SHR, DOCA-salt or renal hypertensivee rats) within one or two weeks of high-fat-cholesterol (HFC) diet feeding by Yamori in 1974, experimental studies on atherogenesis in rats have made a great progress. Especially, the exploitation of a simple method to detect arterial fat deposits in cerebrovascular system (Barium Contrasted Sudan Staining (BCSS) Method) has enabled us to investigate factors affecting cerebrovascular atherogenesis such as hypertension local hemodynamic derangements and hyperlipidemia. Moreover, the establishment of arteriolipidosis-prone rats (ALR) by the selection of substrains of SHR which showed a greater reactive hypercholesterolemia indicated the involvement of genetic factors in atherogenesis. In order to analyze genetic factors of atherogenesis, we have attempted to isolate genetic factors of arterial fat deposition from hypertension by separating the colony of normotensive rats which are prone to develop cerebrovascular fat deposits within a short period.Strain difference in arterial fat deposition in normotensive ratsSix strains of normotensive rats, 20 rats of each, were fed on an HFC diet (containing 5% cholesterol, 20% suet and 2% cholic acid) for 1 year from the age of 30 days. After blood pressure and serum cholesterol level were repeatedly checked, the animals were sacrificed to detect fat deposits in cerebral and mesenteric arteries by BCSS method. Fat deposits were noted only in Wistar-Kyoto (WK) rats, of which 5 and 15% developed fat deposits in cerebral and mesenteric arteris, respectively.Fat deposition in F2 generation obtained by the cross-breeding between normotensive rats and stroke-prone SHR (SHRSP)Therefore, the normotensive WK rats which were proven to be a little more sensitive to fat deposition were mated with 3 female SHRSP with blood pressure 180, 190 and 192mmHg, respectively, to obtain F1 generation from which F2 generation was further produced, and blood pressure, serum cholesterol levels and arterial fat deposits were checked as mentioned above. Blood pressure and cholesterol levels in average in F2 generation were 143±3mmHg (M±SE) and 375±36mg/dl, respectively, after the HFC diet feeding for 3 weeks. Fat deposits in mesenteric and cerebral arteries were noted in 15 and 11 rats out of 26 (58 and 42%), respectively. The F2 rats with cerebrovascular fat deposits showed no difference in blood pressure from those without fat deposits (137±2 vs. 147±2mmHg), but a slightly higher cholesterol level than the latter group (457±60 vs. 304±32mg/dl).Summary with DiscussionThe establishment of ALR which quickly develop hypercholesterolemia (500 and 800mg/dl) within a week of HFC diet feeding indicates that genetic abnormality related to hypercholesterolemia (increased intestinal cholesterol absorption and decreased catabolism) is involved in the proneness to arterial fat deposition, the initial step of atherogenesis. The present experiment has demonstrated that arterial fat deposition develop in F2 generation without hypertension, indicating that the proneness to arterial fat deposition can be genetically separated from the heredity of hypertension. These normotensive F2 rats with arteriolipidosis are hopefully continued to be bred until the establishment of the inbred strain of “normotensive atherogenic rats (NAR)”, the proper model for the analyses on the heredity of atherogenesis.