Understanding Atherosclerosis as "Inflammation Gone Bad"

By Eric Sauter

Linda K. Curtiss has a good sense of humor, a healthy laugh, and an ear for the bon mot—all of which come in handy when dealing with a research subject like atherosclerosis. For example, when asked if there was any sort of worry-free food a person could eat to avoid the nation's number one killer, Curtiss, a professor in The Scripps Research Institute's Department of Immunology, replied, "Red grapes?"

The study of atherosclerosis has undergone something of a revolution over the last quarter century and Linda Curtiss has been deep in those cholesterol swollen trenches since she arrived at Scripps Research in 1974. She did her undergraduate and graduate work at the University of Washington in Seattle, took a couple years off to go skiing in Colorado, and finished her thesis on immunochemistry at the Mayo Clinic in Rochester, Minnesota.

"I left the Mayo Clinic in a blizzard in 1974," she said. "I stepped off the plane in San Diego—those were the days when they rolled the stairs out to meet you—the sun hit my eyes, I smelled the ocean, and I immediately thought, 'This is where I'm going to stay.'"

Curtiss was accepted for postdoctoral work in the Scripps Research laboratory of Tom Edgington (along with another postdoc, Frank Chisari, now a professor at Scripps Research as well) and worked on finding whatever it was in plasma that was altering in vitro lymphocyte proliferation. The answer turned out to be plasma lipoproteins. Curtiss has focused on those lipoproteins for much of the last 33 years.

A Different View

In those three plus decades, Curtiss has built up a body of work that has helped shift the field away from a view of atherosclerosis as a fat problem to something else entirely. "My phrase for it is 'chronic inflammatory response,'" Curtiss said. "Rather than a lipid disorder, atherosclerosis is basically a problem of inflammation gone bad." 

In recognition of her contribution to the new science of atherosclerosis and her "immense contributions to the council for many years," Curtiss was presented with the American Heart Association's Council on Arteriosclerosis, Thrombosis, and Vascular Biology Distinguished Achievement Award last January. The award is for what amounts to a lifetime studying a killer disease. She chaired the council for many years and was active in volunteer work, which, she says, means "going to Washington, advocating for more funding, and talking to legislators, all from a scientific perspective."

The award is also an acknowledgement of her well-established national reputation, a sign post, not a goal post, as she is the first to make clear. What she likes most and what she expects to continue doing for quite some time is science. Curtiss grew up around science—her mother was a high school biology teacher and she had "big fun" dissecting frogs with her—and still enjoys the process: "I love getting up in the morning and going to the laboratory. I love doing science. I honestly don't think I've worked a day in my life."

Curtiss also happens to have high cholesterol, a major risk factor for heart attacks, and takes medication for it.

Now Curtiss is busy filling in her fourth decade searching for a better kind of treatment, one that she hopes will eliminate one of the prime inflammatory villains in the story, a signaling receptor with the chocolate chip cookie name, Toll-like receptor (TLR) 2.

Inflammatory Villain

Toll-like receptors, which are found on many cells including the surface of human endothelial cells (the cells that line blood vessels), are part of the innate immune system. They are known for their ability to recognize and fight microbial disease, and for the fact that they initiate inflammatory responses. It is the latter that plays a significant role in jump starting the process of atherosclerosis and then, quite rapidly, turning it into a life-threatening condition.

In 2005, Curtiss and fellow Scripps Research scientist Peter Tobias took a look at TLR2's involvement in the disease, and found that in mouse models the protein exacerbated the condition through chronic inflammation and does so in a very distinct fashion. With the TLR2 receptor knocked out, there was little atherosclerosis and the mice got less disease. This implicates the receptor—which, in the normal state of things, is still in place—as proatherogenic.

It should be noted here that normal mice, even fat normal mice, rarely get atherosclerosis. Even with high cholesterol, a diet laden with the rodent equivalent of cheeseburgers, French fries, and double chocolate milk shakes, they are still highly resistant to the disease. Obviously, this is some sort of cruel cosmic joke. 

The lab's work on TLR2 was roundly applauded, in great part because it flung open the door to the next phase of research, a search for the natural endogenous compound that activated TLR2. Because if scientists can find that—and a lot of people in addition to Curtiss are looking—they could design a drug that would inhibit the inflammation that contributes so much to the problem in the first place.

"We have five or six candidates," Curtiss said. "These are substances that arise in response to tissue damage, oxidation, the acute phases of infections, things like oxidized lipids and lipoproteins, serum amyloid protein, hyaluronic acid fragments. Oxidized lipids are particularly bad, and a known TLR2 activator. In low-density lipoprotein (LDL) receptor-deficient mice fed a high fat diet, the hyperlipidemia probably activates the TLR2, converting a normal surveillance response into disease."

Risk factors that contribute to TLR2 activation include smoking, a systemic risk factor that touches every vessel in the body by increasing oxidation of lipoproteins, those suspected TLR2 activators. Curtiss is studying the effects of smoking on atherosclerosis with support from the Tobacco-Related Disease Research Program, a program that focuses on the prevention and treatment of tobacco-related disease in California.

Disturbed Flow

The breakdown of the normal process and appearance of disease doesn't happen everywhere, only in those places in the arterial tree that experience disturbed flow—that is, a flow trajectory that isn't a straight line. The aortic arch is one of those places where TLR2 is expressed on the endothelial cells and where lesions form. 

"Expression of TLR2 explains why a specific site in the system forms lesions, but it doesn't tell us how," she said. "We know that the gene is saying that areas of disturbed flow are somehow different from other parts of the system. When we look at these areas, we see macrophages moving in and out—they're basically keeping the location under surveillance. If the mouse never becomes hyperlipidemic, the lesions won't form. If the animal is hyperlipidemic, however, the macrophages stay and the normal repair mechanism becomes a dangerous pathology."

The changes soon begin to snowball. The macrophages bring in more cells and load up the endothelial walls with cholesterol; the genes change expression and cells begin to accumulate the circulating lipids. Eventually, when enough accumulate in one place, some of these cells die and break off. When that happens, there's classic plaque rupture that can lead to a heart attach or stroke.

In mice, these atherosclerotic changes are extraordinarily rapid. "Within a week of consuming a high fat diet, the mice dramatically increase the amount of TLR2 expressed," Curtiss said. "Within a few weeks, you will start to see the type of lesions that are often seen in human adults. "

What they need to understand now, Curtiss explained, are the mechanics of this disturbed flow, why the body reacts to it in this fashion, and what other changes are going on that contribute to the activation of endothelial cell TLR2 and the onset of atherosclerosis.

"Once we know that, we can focus on some of these changes as potential drug targets," she said.

Ambitious Goals

There is already a big push in the industry to find just the right target to treat a disease that kills close to a million people a year in the United States alone. It hasn't been easy. Last December, Pfizer stopped work on torcetrapib, a compound to treat heart disease by raising HDL levels, a highly complex molecule that has proven difficult to work with. HDL returns cholesterol from peripheral tissue to the liver and from there sends it out of the body; LDL, the bad cholesterol carrier, oxidizes and accumulates it.

Curtiss herself is working on new ways to raise levels of HDL, which, as the Pfizer experience suggests, is challenging in the extreme.

Difficult it may be, but Curtiss has her sights set even higher. "We're going to get rid of cardiovascular disease as the number one killer of people in this society," she said. "The more we understand it, the better we can treat it."

Adding to that understanding is what she loves to do. And she enjoys sharing that knowledge, too.

"Human physiology evolved at a time when it was absolutely necessary to conserve cholesterol," she said. "Because we ate things that had little cholesterol, the cave man didn't have to worry about high cholesterol—he wasn't obese and didn't have diabetes. Now we have to figure out a way to get rid of it. We have to change our diet and exercise and get rid of these other risk factors. So, when I give lectures, I show an evolutionary cartoon of an ape walking and on the other end, a picture of an obese man with a very large stomach."

In other words eat red grapes and no more cheeseburgers.

Send comments to: mikaono[at]scripps.edu

"Rather than a lipid disorder, atherosclerosis is basically a
problem of inflammation gone bad," says Professor Linda K. Curtiss.