An important step to victory over atherosclerosis
In experiments on mice and rabbits, Johns Hopkins University researchers have developed a method for blocking the synthesis, transport and breakdown of abnormal cholesterol, preventing the development of atherosclerosis – a disease that is the main cause of myocardial infarction and stroke in humans.
Atherosclerosis is manifested by the formation of so-called cholesterol plaques on the inner surface of the vessel walls. As a result, vascular walls lose elasticity and thicken, which, in turn, leads to a decrease in vascular lumen and deterioration of blood supply to organs and tissues.
The authors claim that the cause of cholesterol metabolism disorders in the body is glycosphingolipid, a compound that is part of the membranes of all cells of the body and participates in the regulation of cell growth. They came to this conclusion based on the results of experiments on animal models of atherosclerosis, in the feed of which a compound known as D-PDMP blocking the synthesis of glycosphingolipid was added (not every chemist will pronounce its full name without hesitation: D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol).
The first series of experiments was carried out on genetically modified mice that do not have a protein that plays a key role in the breakdown of fats, and, accordingly, are predisposed to the development of atherosclerosis. Such animals were kept for several months on a fat-rich diet, up to 20% of whose calories were represented by triglycerides. A low dose of D-PDMP was added to the feed of one of the three groups of animals, a high dose of D-PDMP was added to the feed of the second group, and the third group received a placebo.
Subsequent measurement of the thickness of the aortic wall – the largest artery of the body – showed striking differences between the three groups. As expected, the aortic walls of the control group mice were thickened due to massive fat deposits and calcifications. The aortic walls of animals receiving a low dosage of D-PDMP were significantly thinner and did not cause significant narrowing of the vessel lumen. The aorts of the third group of mice receiving a high dosage of D-PDMP were indistinguishable from the arteries of healthy animals. At the same time, the speed and uniformity of blood flow in the aorta of the animals corresponded to the state of the vascular wall.
The study of animal liver cells, which is the main organ of fat synthesis and breakdown, also revealed striking differences between the expression levels of several genes involved in the regulation of cholesterol metabolism. The activity of these genes is manifested by the levels of their protein products – liver enzymes. The use of D-PDMP significantly increased the levels of two enzymes responsible for maintaining lipid homeostasis of the body by regulating the ability of cells to break down cholesterol and other fats. D-PDMP therapy also stimulated the activity of an enzyme that ensures the excretion of fats from the body by converting them into bile.
In the second series of experiments, the researchers compared the effects of D-PDMP therapy on two groups of healthy rabbits kept on a fat-rich feed. One of the groups of animals received D-PDMP, the second was used as a control group.
The use of fat-rich feed led to the development of typical symptoms of atherosclerosis in animals of the control group: the appearance of atherosclerotic plaques on the inner surface of the arterial walls, as well as a decrease in elasticity and a decrease in the lumen of blood vessels. Cholesterol levels in the blood of these animals increased 17 times. At the same time, rabbits treated with D-PDMP did not develop atherosclerosis. The cholesterol content in their blood also remained within the normal range.
According to the authors, modern drugs for lowering cholesterol in the blood affect the problem only through one mechanism. They either block the synthesis of cholesterol, or reduce its absorption by the body. However, atherosclerosis is a multifactorial problem, to solve which abnormal cholesterol metabolism must be affected at its different stages simultaneously.
Suppression of glycosphingolipid synthesis by D-PDMP provides the desired result. Apparently, the experimental drug acts by interfering with a complex of genetic mechanisms that regulate fat metabolism at different levels: from the absorption of cholesterol contained in food by cells of the gastrointestinal tract and ending with its transport to tissues and organs, as well as cleavage in the liver and excretion from the body.
The experimental drug D-PDMP, currently widely used in basic research to block and study the growth and other basic functions of cells, is considered safe for animals. This is also evidenced by the absence of any side effects in animals treated in the study with a dosage of D-PDMP, 10 times higher than the minimum effective dose. In the near future, the researchers hope to conduct a clinical trial of the drug in which D-PDMP will act as an active ingredient.
Article by Chatterjee et al. Inhibition of Glycosphingolipid Synthesis Ameliorates Atherosclerosis and Arterial Stiffness in Apo E-/- Mice and Rabbits Fed a High Fat and Cholesterol Diet is published in the journal Circulation.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on Johns Hopkins University materials:
Johns Hopkins Scientists Alter Fat Metabolism in Animals to Prevent Most Common Type of Heart Disease.
25.04.2014