Recruitment of leucocytes to atherosclerotic lesions in vivo
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: More cigarette smokers die of a heart attack than die of lung cancer or any other single cause. There is very good evidence from studies in animals that oxidative damage to the large, cholesterol-carrying molecules in the blood stream, especially low density lipoproteins (LDL), plays an important part in atherosclerosis, the underlying disease of the arteries that ultimately leads to a heart attack. The oxidatively damaged LDL (OxLDL)is then taken up by cells in the wall of the artery, and that is how the cholesterol concentrations build up. Another effect of OxLDL is to attract circulating white blood cells (mainly monocytes) into the damaged artery wall, which further accelerates the disease process. While a good deal has been learned about the molecules to which monocytes stick and the molecules that draw them into the artery wall, the relative importance of these has yet to be properly assessed in the whole animal. Methods simply have not been available that are sensitive enough for this kind of study. We in this laboratory have now developed such a method, one that is sensitive enough to detect even one genetically marked cell in the presence of 1 million genetically unmarked cells. The method takes advantage of the remarkable sensitivity of the polymerase chain reaction (PCR) which uses an enzyme in such a way as to amplify a single copy of a gene into millions of copies in just a few hours. We take advantage of the fact that only males have a copy of the testis-determining gene (sry gene) which resides on the Y chromosome, the chromosome that is exclusively found in males. The "trick" is to transfuse monocytes taken from a male donor mouse into the blood stream of a female recipient mouse and determine how many male cells appear in the wall of the artery after a given time interval. Using this method we have shown for the first time in vivo that 2 of the compounds suspected on the basis of in vitro studies to be important in recruiting monocytes to lesions are in fact involved also under in vivo conditions. These are tumor necrosis factor-and interleukin-1. Our theory is that the very first thing that happens is a buildup of OxLDL in the artery wall, which in turn causes monocytes from the blood to enter the artery wall. Since these monocytes can then themselves contribute to further oxidation of LDL and, indirectly, speed up the recruitment of still more monocytes, the damage to the artery might well spiral out of control. We will test directly whether administration of compounds that block oxidation of LDL decreases the rate at which monocytes enter the artery wall. We will also explore the role of MCP-1 and the nature of the regulation of MCP-1. Specifically, we will test whether a new class of drugs, the thiazolidinones, inhibits monocyte recruitment and whether that leads to inhibition of the formation of new lesions in the artery wall. Finally, we will test the hypothesis that cigarette smoking increases the rate of monocyte entry into lesions of LDL receptor deficient mice and by so doing accelerates the progression of atherosclerotic lesions.