Scientists have discovered a significant new clue to help explain why some people develop clogged heart arteries, which can lead to heart attacks.
Researchers at Genentech Inc. in South San Francisco and at the University of Chicago have found striking similarities in the molecular structures of a protein involved in blood clotting and a protein called apolipoprotein(a), contained in fat-like substances that can build up in the arteries.
The findings, reported in the current issue of the British journal Nature, suggest that apolipoprotein(a) may interfere with the body's ability to dissolve substances that clog arteries.
Thus, the new data may open up a new field of heart disease prevention research as well as help account for the tendency of individuals with high levels of the protein to develop obstructed heart arteries.
The report was one of three developments this week in the battle against heart disease.
The researchers, using recombinant DNA technology, determined for the first time the genetic structure of apolipoprotein(a), or apo(a), a mysterious molecule discovered about 25 years ago. Such apolipoproteins are contained in complexes of fat-like substances in the bloodstream, along with cholesterol and other fat molecules called lipids.
High levels of apolipoprotein(a) have for some time been associated with the development of atherosclerosis, or hardening of the arteries, particularly in individuals who have excessive amounts of cholesterol and other lipids in their blood. But it was unclear why this was the case, according to James E. Tomlinson, one of the Genentech researchers.
When the scientists completed analysis of the gene structure, they were astounded to discover an "extreme similarity" to the structure of plasminogen, a blood protein involved in dissolving blood clots. Almost all people have large amounts of plasminogen in the circulation. Apolipoprotein(a) "looks like a plasminogen gene gone awry," the report said. For different parts of the molecules, the two are between 78% and 100% identical.
On the basis of the new information, it appears that apolipoprotein(a) may interfere with the body's ability to eliminate microscopic blood clots that form in the heart arteries or, paradoxically, lead to the buildup of additional blood clots, according to Tomlinson.
This is because apolipoprotein(a) may both mimic the plasminogen molecule and at the same time counteract its actions. The researchers suspect that this is the case because apolipoprotein(a) is missing an amino acid that is present in plasminogen and is crucial to plasminogen's ability to break down blood clots. But Tomlinson cautioned that such hypotheses must be investigated in further studies.
In an editorial for Nature commenting on the research, two Nobel Laureates hailed the revelation of the protein's structure as "astounding."
"These dramatic findings may provide the long-sought link between lipoproteins and the clotting system," said Dr. Michael S. Brown and Dr. Joseph L. Goldstein of the University of Texas Southwestern Medical Center in Dallas, who shared the Nobel Prize in 1985 for pioneering lipid research. "It is hard to imagine that nature is only teasing us and that the resemblance . . . has no functional consequence."
Meanwhile, Finnish researchers reported in today's New England Journal of Medicine that the prescription drug gemfibrozil reduced cholesterol levels and the incidence of heart attacks and cardiac deaths in middle-aged men with high cholesterol in their bloodstream. But the death rate from all causes was not significantly changed by the treatment.
The five-year Helsinki heart study involved more than 4,000 men. The results are in accord with earlier studies showing that similar benefits can be obtained with other prescription drugs.
Also this week, researchers at the University of California, San Diego, School of Medicine, led by Dr. Daniel Steinberg, announced that another prescription drug, probucol, can significantly reduce the development of atherosclerosis in rabbits by interfering with cholesterol buildup on the walls of arteries.
The beneficial effect on the arteries occured even though the concentration of cholesterol in the rabbits' bloodstreams did not change, the scientists said. The UC San Diego researchers said their work may lead to the development of human therapies for atherosclerosis unrelated to the reduction of blood cholesterol levels.