Local Hormones and the Atherogenic Uptake of Low Density Lipoprotein in vivo

Summary

Atherosclerotic disease begins with the accumulation of atherogenic plasma proteins, predominantly low-density lipoprotein (LDL), in the walls of susceptible arteries. One determinant of this accumulation is the LDL concentration in the blood. We are investigating other factors which may influence the uptake of LDL and of fibrinogen, another atherogenic plasma protein, by artery walls from the circulating blood; the mechanism(s) of this uptake; and the rate and magnitude of the accumulation of the atherogenic plasma components in arteries. In order to model human atherogenesis as closely as possible, the experiments are in vivo using rabbits in which the initial stages of atherogenesis appear to be similar to those in man.

Up to the present the principal new observations are as follows:

• (1) In anaesthetized rabbits, the rate of uptake of LDL related to lumenal surface area is similar in large arteries and large veins, whereas the progressive accumulation of LDL is significantly greater in the arteries than in the veins. This suggests that the accumulation of LDL in arteries but not in veins depends less on haemodynamic than on other differences.

• (2) Selective desialation of the endothelial surface of arteries in vivo greatly accelerates their LDL uptake. This suggests that the rate of accumulation of LDL may be limited by, inter alia, the exceptionally high densities of sialic acids which we had previously demonstrated on the lumenal surface of arteries and veins in several species including man (umbilical vein).

• (3) In conscious, restrained rabbits, intravenous infusions of histamine sufficient to produce inter-endothelial gaps throughout the venular systems did not increase the rate constant of the disappearance of LDL from the circulating blood. This makes it improbable that significant quantities of LDL pass out of the blood into vessel walls between endothelial cells and indirectly supports the evidence that LDL leaves the plasma by transcytosis through the endothelial cells.

• (4) More recently we discovered that in anaesthetized rabbits the rate of uptake of LDL, methylated to prevent its removal by high-affmity receptors (m-LDL), is significantly increased by noradrenaline and by adrenaline within their physiological concentration ranges in the blood. This appears to be the first direct demonstration of a potentially atherogenic effect of the catecholamines in vivo and at physiologically relevant concentrations.