Oxysterol incorporation into rat aorta resulting in elastin compositional changes.

The incorporation of dietary cholestan-3 beta,5 alpha,6 beta-triol (triol) into rat thoracic aortic tissue and changes in amino acid composition of the elastin were investigated to identify the cytotoxic properties of the triol. Weanling male Sprague-Dawley rats were fed the following diets for three months: (i) normal chow, (ii) normal chow with 1% (w/w) cholesterol added, or (iii) normal chow with 0.9% (w/w) cholesterol and 0.1% (w/w) triol added. Triol levels in the blood and in the thoracic aortic tissue were measured. Compositional changes of elastin were also determined. After three months on the triol-containing diet, triol was found in the thoracic aorta but was not detected in the blood. Amino acid analyses of the aortic tissue elastin revealed that the proline levels in the triol-fed animals were significantly greater than in the other two diet groups, while the elastin levels of leucine, aspartate, arginine, and phenylalanine decreased significantly. The mechanism for these observed changes induced by triol may reflect alternate splicing of elastin messenger ribonucleic acid (mRNA) resulting in structual changes in the elastin molecule. Dietary triol does contribute to tissue triol content and is associated with aortic elastin compositional changes. How these changes may contribute to the development of cardiovascular disease is not known.

Haloperidol administration to rats during pregnancy induces permanent alterations in serum lipoprotein patterns of progeny.

The rat is notoriously resistant to vascular disease, but administration of haloperidol prenatally to the pregnant dam results in hyperlipidemic changes in F1 and F2 progeny. Total serum cholesterol concentrations in the F1 males reach levels three or more times greater than controls by one year of age. The phenomenon indicates a link between dopaminergic elements of the autonomic nervous system and cholesterol metabolism, a phenomenon heretofore unrecognized. Transfer of the hypercholesterolemia into the second generation further suggests that haloperidol induces a permanent change in the genetic control of lipoprotein metabolism. Although the observations are preliminary, they warrant consideration when administering the drug to pregnant women.

Modification of the pulmonary connective tissue developmental response in the neonatal rat by ciclosporin.

Neonatal rat pups were treated either with ciclosporin at 10 mg/kg/day dissolved in olive oil (experimental) or with pure olive oil (control). Lung protein biosynthesis was evaluated in a protocol which involved the measurement of total accumulated protein, collagen and elastin. Four time points were studied in the first 21 days of life, 12 animals contributing to each point (6 control and 6 ciclosporin). Ciclosporin levels in the treated group ranged widely (2,000-4,000 ng/ml). There were significant differences in total body weight and lung weight in treated vs. controls during and after the first week. DNA contents per unit wet weight varied significantly during the second week of life, indicating increased cellularity of the ciclosporin-treated animals. Associated with this was an increase in the lung protein/DNA ratio as well as the elastin/DNA ratio in the control animals, but not in the treated ones. The lung collagen/DNA ratio was not as dramatically affected by the ciclosporin treatment. However, the collagen content per unit wet weight of lung tissue was increased in the ciclosporin-treated animals at 15 days of life. We conclude that ciclosporin has a marked effect on lung connective tissue metabolism in early life, the long-term effects of which are unappreciated and undocumented but may well be of vital importance in the lungs of long-surviving organ transplant patients.

Association of cholesterol concentrations in low-density lipoprotein, high-density lipoprotein, and high-density lipoprotein subfractions, and of apolipoproteins AI and AII, with coronary stenosis and left ventricular function.

We examined the association of cholesterol levels in serum lipoprotein fractions, as well as of serum apolipoprotein-AI (apo-AI) and apo-AII levels, with coronary artery stenosis (CAS) and left ventricle function in a group of 43 patients with angina pectoris (33 men and 10 women) subjected to angiography. Cholesterol level in VLDL, LDL, HDL2, and HDL3 fractions was determined after separation of these fractions by density gradient ultracentrifugation. HDL-cholesterol is the sum of cholesterol in HDL2 and HDL3. Cineangiography yielded scores for CAS and for left ventricle ejection fraction (LVEF). On univariate regression CAS was correlated weakly with LDL-cholesterol (positive) and with HDL3-cholesterol and HDL-cholesterol (negative), and more strongly with LDL-cholesterol/HDL-cholesterol (positive), but not with HDL2-cholesterol. LVEF was correlated positively with HDL3-cholesterol, HDL-cholesterol, apo-AI, and apo-AII. Of other "risk factors," none was correlated with CAS, and a history of previous myocardial infarction (PMI) was the only one significantly correlated with LVEF. CAS itself was also correlated negatively with LVEF. In multiple regression analysis with two or three independent variables, the relation of HDL(3)-cholesterol with CAS remained significant when other risk factors were taken into account. LVEF remained related positively with HDL(3)-cholesterol, apo-AI, or apo-AII, when either of them was tested in combination with other risk factors; of these only PMI made a significant independent contribution. Conclusions for this patient group (with low HDL-cholesterol): HDL3-cholesterol, and not HDL2-cholesterol, is informative for CAS; HDL(3)-cholesterol, apo-AI, or apo-AII, as well as CAS and PMI, are associated with LVEF.(ABSTRACT TRUNCATED AT 250 WORDS)

Endogenous cholesterol synthesis, fecal steroid excretion and serum lanosterol in subjects with high or low response of serum cholesterol to dietary cholesterol.

In this study we addressed the question whether hypo- and hyper-responders to dietary cholesterol differ with regard to the flexibility of endogenous cholesterol synthesis after changes in cholesterol intake. Whole-body cholesterol synthesis was measured as faecal excretion of neutral steroids and bile acids minus cholesterol intake. In addition, we determined serum concentrations of lanosterol, a precursor of cholesterol and a possible indicator of cholesterol biosynthetic activity. The study was carried out with 2 hyper- and 4 hypo-responders; these subjects had shown a consistently high or low response of serum cholesterol to a decrease in dietary cholesterol in two previous experiments. The subjects received controlled high- (on average 697 mg of cholesterol per day) and low-cholesterol (109 mg/day) diets for periods of 4 weeks in succession; cholesterol was the only dietary variable. The two hyper-responders again showed a significant decrease in serum cholesterol. There was essentially no decrease in serum cholesterol in three of the four hypo-responders. The decrease in cholesterol intake caused an increase in cholesterol synthesis in five out of the six subjects. There was no association between the individual change in serum cholesterol and the change in cholesterol synthesis. Transfer from the high- to low-cholesterol diet caused an increase in serum lanosterol in all subjects. The increase was 3- to 4-fold higher in three out of the four hypo-responders than in the two hyper-responders. We tentatively suggest that this study provides some evidence that the flexibility of cholesterol synthesis is involved in the responsiveness to dietary cholesterol.

Diurnal changes in serum triglycerides as related to changes in lipolytic enzymes, lipoproteins and hormones in patients with primary endogenous hypertriglyceridaemia on a carbohydrate-rich diet.

Parameters of diurnal triglyceride (TG) metabolism were investigated in 5 subjects with primary endogenous hypertriglyceridaemia and compared with those of normal subjects studied previously. The patients were in a steady state on a carbohydrate-rich diet (meals at 9.00, 13.00 and 17.00 h). Serum TG showed a wavelike pattern with a maximum at around 17.00 h. Post-heparin lipoprotein lipase (LPL) activity in the fasting state was not different from that in normals, but failed to show the normal increase in the fed state (16.30 h). This was due to the inability of patients to increase their adipose tissue (AT)-LPL activity in the course of the day. AT-LPL activity was throughout the day lower than in normal subjects. Skeletal muscle LPL activity was low and showed no diurnal change, equalling our findings in normal subjects. Low density lipoprotein cholesterol and high density lipoprotein (HDL) cholesterol concentrations showed no diurnal change. However, HDL phospholipids increased significantly in the course of the day.

Serum lipoproteins in cholesterol-fed pigs after partial ileal bypass.

Partial ileal bypass (PIB) surgery was performed in hypercholesterolaemic mini-pigs and Yorkshire pigs fed a semipurified diet containing 1% (W/W) of cholesterol. PIB drastically reduced serum total cholesterol and phospholipid concentrations and the cholesterol: phospholipid ratio in spite of continuation of cholesterol feeding. The relative distribution of cholesterol between serum lipoproteins was affected by PIB; the surgical treatment caused an increase in the ratio of high-density lipoprotein (HDL) to low-density lipoprotein (LDL) cholesterol. Serum apo B and apo A levels were rapidly decreased by PIB. The operation induced a decrease in the cholesterol: apo B and cholesterol: apo A ratios. It is suggested that the pig is a suitable animal model to study PIB-induced changes in lipoprotein metabolism.

Diet, lipoproteins, and the progression of coronary atherosclerosis. The Leiden Intervention Trial.

We studied the relation between diet, serum lipoproteins, and the progression of coronary lesions in 39 patients with stable angina pectoris in whom coronary arteriography had shown at least one vessel with 50 per cent obstruction before intervention. Intervention consisted of a two-year vegetarian diet that had a ratio of polyunsaturated to saturated fatty acids of at least 2 and that contained less than 100 mg of cholesterol per day. Dietary changes were associated with a significant increase in linoleic acid content of cholesteryl esters and a significant lowering of body weight, systolic blood pressure, serum total cholesterol, and the ratio of total to high-density lipoprotein (total/HDL) cholesterol. Angiographic examination was performed after 24 months; angiograms were assessed visually (with blinding) and by computer-assisted image analysis. Both types of assessment indicated progression of disease in 21 of 39 patients but no lesion growth in 18. Coronary lesion growth correlated with total/HDL cholesterol (r = 0.50, P = 0.001) but not with blood pressure, smoking status, alcohol intake, weight, or drug treatment. Disease progression was significant in patients who had values for total/HDL cholesterol that were higher than the median (greater than 6.9) throughout the trial period. No coronary-lesion growth was observed in patients who had lower values for total/HDL cholesterol (less than 6.9) throughout the trial or who initially had higher values (greater than 6.9) that were significantly lowered by dietary intervention.