Science Editor

Whether you call it a conspiracy or a ballet dance, atherosclerosis is a devious killing machine that pits one molecule against another. Hardening of the arteries, as it's better known, atherosclerosis is the prime cause of mortality in Western industrialized countries.

Lining up the rap sheet of these heart-disease risk factors suggests that in a few cases - smoking, overeating, lack of exercise, high cholesterol - victims may well have only themselves to blame for their demise. Overriding these sins of indulgence are the main and unavoidable risks, to wit: being male, female-gender menopause, hypertension, diabetes mellitus, family history.

The inner endothelial lining (or intima) of important arteries paves this live-or-die battlefield. Its opening shot is the laying down of lipid deposits, which narrow the arterial lumens. This pinches off their full flood of blood to nourish heart (failure), brain (stroke) and legs (gangrene). Pumping that liquid nutrient through its diminishing caliber pounds and punishes those blood vessels, especially at points where they go from gentle curves to sharp branches and preferred plaque deposition.

The thick smooth-muscle cells (SMCs) of an artery respond to the presence of lipid by proliferating under the influence of platelet factors. An arteriosclerotic plaque forms at the inner site, consisting of SMCs, immune system leukocytes and still more lipid.

Molecular geneticist Joachim Herz, in the molecular genetics department at the University of Texas Southwestern Medical Center in Dallas, is senior author of a paper in Science, dated April 11, 2003, and titled: "LRP: Role in vascular wall integrity and protection from atherosclerosis."

"We have identified a protein called LRP - low-density lipoprotein receptor-related protein - that helps ward off atherosclerosis in mice," Herz told BioWorld Today. "Normally," he added, "when high cholesterol levels weaken blood vessels, the body attempts to patch the problem area by sending a growth factor that calls in smooth muscle reinforcements. However, these SMCs thicken and harden the arteries, and worsen the atherosclerotic onset. LRP, however, has the ability to bind with the growth factors' receptors and restrain this pathogenic process."

When Growth Factors Go Haywire, Watch Out!

"In genetically engineered mice from whose genome we have knocked out vascular LRP, the growth factor goes haywire, allowing smooth muscle cells to build up to excess. Our treatment with the drug Gleevec," Herz continued, "which takes over LRP's role of inhibiting the growth factor, had a profound protective effect on the mutant mice, even when they were fed a high-cholesterol diet. Interestingly," he noted, "Gleevec - a new drug that has been remarkably successful for treatment of certain human cancers - was originally developed in the early 1980s against restenosis in atherosclerosis.

"Our paper shows that transgenic KO animals lacking LRP already develop atherosclerotic lesions over a murine lifetime of about two years without our having to add a high-cholesterol diet. However, in order to be able to do experiments prospectively in a more amenable time frame, we fed the animals a cholesterol-rich diet to accelerate the disease process, which took them from six weeks to two months.

"These lipoprotein particles enter the vascular wall, forming a fatty streak to start with," Herz recounted. "Then come the repair and clearance processes, which involve the invasions by immune system monocytes and macrophages to the site from the circulation. Also, the uptake of deposited lipid particles by cells of the vascular wall lead to engorgement of the macrophages and smooth muscle cells, which transforms them into foam cells. They are a large part of the atherosclerotic plaque lesions.

"Cholesterol is a component of those lipoprotein particles, which are small enough so they are being taken up by the vessel wall," he said. "The cholesterol cannot be metabolized or locally broken down, so it's taken up by other cells in the wall, such as macrophages or smooth-muscle cells. They accept this cholesterol but can't get rid of it. Then they become those large lipid foam cells, which extend to a new function in controlling the signaling ability of the PDGFR [platelet-derived growth factor receptor]. It sends mitogenic signals to cells on which it is expressed. In this case, PDGFR signaling would promote the proliferation of smooth-muscle cells in the artery, and (counter-intuitively) enhance development of atherosclerosis. It promotes those muscle cells to an excess, because this signal is overshooting the KO mouse's LRP-deficient vessel wall. Normally this is a process that occurs in wound healing and repair. It also plays a big role, for instance, in wound healing of the skin.

"There are several mechanisms by which the disease process leads to atherosclerosis and heart trouble. This can only relate to damage occurring in the vascular walls from various mechanisms. High LDL [low-density lipoproteins] and high blood sugar can be involved in this. The LDL receptor-related protein in the SMCs appears to be effectively functioning as a brake, which keeps the PDGF receptor in check," he observed. "Thus it prevents abnormally high activation of an SMC proliferative and repair process. This in response to the lesions of the vascular wall, which likely are being initiated by high cholesterol."

Gleevec Moves To Murine Center Stage

"We gave Gleevec in these experiments as a proof of principle because it was readily available for clinical use," Herz continued. "We tested the activation of the PDGFR tyrosine kinase activity, which was responsible for the increased lesion development. We took the KO animal, from which LRP was knocked out and PDGFR activity elevated, and fed the mice tyrosine kinase inhibitor [Gleevec], which would inhibit PDGFR. Abnormal activation of this PDGFR in fact, was an important disease development factor in those mice.

"There are drugs out there that are more specific than Gleevec," Herz observed. "Gleevec is a well-characterized inhibitor that is on the market and in clinical trials. The point is I don't want to push tyrosine kinase inhibitors to treat atherosclerosis. What we have shown here is the principle that it can work in this particular model in which we have an abnormally high activation of PDGFR signaling. But we don't have any really specific data with which I would say," he concluded, "how useful this is going to be in a human."