By David N. Leff
Hardening of the arteries — i.e. atherosclerosis — strikes people in middle age or old age. Right?
Well, yes and no. Atherosclerosis is a disease that occurs over decades. It takes the form, at first, of a sludge that builds up at a site in an artery's inner wall that has been injured by, for example, high blood pressure, chronically elevated cholesterol, smoking or exposure to other toxic substances. When fatty lipoproteins build up at such lesioned sites, hard, blood-blocking plaques develop, capped eventually by blood platelets.
"What usually kills humans," observed cardiovascular-disease biologist Israel Charo, "is an acute event of platelet-mediated thrombosis, which occurs on the surface of these plaques."
It may take years or decades for this buildup of artery-damming plaque to reach critical mass, so it has never been possible to pinpoint the initial onset of this process in a human patient, Charo pointed out, "because we only see autopsies in humans."
He cited one serendipitous glimpse that occurred nearly half a century ago.
"There are some well-known studies from the Korean War," he told BioWorld Today, "in which young men of 18 to 25 years of age who were killed and had autopsies done, showed evidence of early atherosclerosis. Namely, the tell-tale, foam cell-laden fatty streak on an affected arterial wall. At the time, it was very surprising that such young men would have the hallmark of this disease, which is assocated with people much older. So, atherosclerosis begins at a very early age in humans."
Charo is associate director of the Institute of Cardiovascular Disease, at San Francisco General Hospital. His research focus is a factor in the blood, a chemokine that recruits white blood cells to the scene of inflammation in the body. It's called monocyte chemoattractant protein (MCP). This molecule specializes in enlisting monocyte/macrophages, which scavenge deleterious debris in the body.
Because MCPs are found in atherosclerotic lesions, Charo and others suspected them of overdoing their useful mission of moderating inflammation, and aggravating plaque formation instead. "This is one of the very early events in atherosclerosis," Charo pointed out.
Four years ago, he and his team cloned the receptor for human MCP-1, and more recently the murine version of this chemokine. Now, they have raised a colony of knockout mice that lack the gene for this receptor, which they designate CCR2. Without CCR2, the mice cannot respond to MCP-1; presumably, this lack would lessen the atherosclerotic process.
That is what Charo and his team set out to confirm. Their results appear in today's Nature, titled, "Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis." Charo is the paper's senior author.
Strategy For Knocking Out Hardened Arteries
"We took those CCR2-minus mice," Charo recounted, "and cross-bred them with the apolipoprotein-E (apo-E) knockout mouse, which has a great propensity to develop atherosclerosis." They also crossed another cohort of apo-E knockout animals with CCR2-plus mice.
Both groups of animals ate "Western diets" that is, diets high in fats and cholesterol. Their aortas were then analyzed for signs of atherosclerosis.
"Our working hypothesis was that if MCP-1 was indeed important to bringing monocytes into the blood-vessel wall, then we would see fewer monocytes in an animal's lesion, because its CCR2 receptor was gone, so its monocytes could not respond," Charo said. "And, indeed, that is what we found.
"Although one can find MCP-1 in the vessel wall, that's not proof that it's cause and effect for recruitment of monocytes," he added. "So, that's what we were trying to illuminate.
"MCP-1 is also made in response to the presence of oxidized lipids," he continued. "So what may be going on is that the atherogenic process is a pathological extension of the inflammatory process."
Charo pictured the mechanism (proposed by others) as "oxidized lipids inducing the synthesis of MCP-1, which in turn recruits monocytes and macrophages into the arterial wall, to try and deal with inflammatory situations. There they become trapped, engorged with the lipids, and turn into foam cells. These then actually make more MCP-1 themselves, and recruit new monocytes into the wall, in what's likely to be a positive feedback loop.
"We've identified a mechanism," Charo went on, "whereby oxidized lipids attract monocytes to the vessel wall. Clinically, this paper provides a rational basis for developing antagonists to the MCP-1 receptor, for use as therapeutics. This should encourage pharmaceutical companies to ramp up their efforts to find an antagonist for this CCR2 receptor."
He added that a number of companies "are, and have been, setting up high-throughput screening assays to look for such antagonists."
Save Inflammatory Baby From MCP Bath Water
Research pathologist Russell Ross, Director of Vascular Pathology at the University of Washington, in Seattle, originated the response-to-injury hypothesis of atherogenesis.
"The CCR chemokine," Ross told BioWorld Today, "is an important component that plays a role in attracting monocytes into the wound and inactivating them. As a consequence, the ability described by Charo would offer one an opportunity to modulate the process of atherogenesis itself.
"The therapeutic implication," he observed, "is very important, because this offers another approach to specifically modify the response in the artery wall."
Ross added a caveat: "One of the questions it raises is, how is that going to affect inflammatory responses that you don't want to impede, that are protective?
"MCP-1," he said, "is not unique to the artery wall. It also is involved in other inflammatory responses. So the question is, is it possible to titrate that response by a CCR2 antagonist, without inhibiting inflammation elsewhere? It's certainly worth trying. If it works, then you're in good shape.
"There is a lot of redundancy in most of these systems," Ross concluded, "and therefore there are other ways to get these cells into sites where you want them. So, you don't need 100 percent inhibition of the inflammatory response to protect against atherosclerosis. What you need is a reasonable, decreased response." *