Discoveries

Protein shows promise in reversing plaque

Photo by Jon Gilbert Fox

Mulligan-Kehoe studied plaque deposits in mice.

By Tina Ting-Lan Chang

If only "atherosclerosis" weren't such a tongue-twister. The disease kills more Americans than cancer but has nowhere near the frightening ring for most people as the word "cancer." Atherosclerosis involves a buildup within the arteries of fatty deposits called plaque. The arterial wall compensates for the blockage in the blood flow by expanding around the plaque deposits. As a result, atherosclerosis is a "silent" disease until the deposits overwhelm this compensatory mechanism.

A heart attack or stroke caused by a blockage may be the first sign of the disease. By then, irreversible damage has often occurred. Treatment options include lifestyle changes (such as diet, exercise, and smoking cessation), medication, and surgery. There may one day be another option on that list.

Fat: In a paper published in Circulation Research, DMS's Mary Jo Mulligan-Kehoe, Ph.D., and colleagues revealed a possible new way to reduce plaque. The team administered a protein molecule called rPAI-123 to mice that had been fed a high-fat diet to foster the creation of plaque deposits. The protein inhibited angiogenesis -the growth of new blood vessels-in the plaque-filled arteries, affecting the plaque's growth and stability. Of particular note was the fact that the protein also reduced the cholesterol in plaque deposits by an impressive 49%. The authors hailed this as "a dramatic effect."

Protein: Mulligan-Kehoe explains that rPAI-123 is a truncated form of a parent protein called PAI-1, whose role in angiogenesis remains controversial. "In everything you read about atherosclerosis relative to PAI-1," she says, "they cannot put a handle on whether it's pro- or anti-angiogenic"-that is, whether it promotes or inhib-its the formation of blood vessels. And, she adds, "they've looked at it in plaques and they can't tell you whether it's protective or causes plaque progression."

So Mulligan-Kehoe, with funds from two NIH grants plus Philips Imaging, set out to identify the functions of PAI-1. The researchers started by cutting away certain regions of the protein. They found that truncated forms were pro-angiogenic if they contained a certain domain, such as rPAI-Hep23. But when that domain was removed, the truncated protein became anti-angiogenic, such as rPAI-123.

In addition, using samples of plaque obtained from DHMC patients, Mulligan-Kehoe has shown the presence of both native and truncated PAI-1 in some patients, suggesting that truncated forms of the protein are physiologically relevant.

Lab: The finding that different forms of PAI-1 can be pro- or anti-angiogenic may have application to other diseases as well. Mulligan-Kehoe's lab is also looking at how rPAI-Hep23 can improve blood circulation in patients with diabetes. But as excited as she is about the therapeutic potential of rPAI-123, Mulligan-Kehoe is eager to continue using it as a tool to study PAI-1. "I just love the science," she says.