New drugs could be developed to treat hardening of the arteries, say American scientists. Hardening of arteries - atherosclerosis - a major cause of heart disease, has been thought to be caused by complex interactions between excess cholesterol and swollen heart and blood vessels.
But now scientists from the University of California, San Diego School of Medicine, along with other American colleagues, believe a forerunner to cholesterol subdues inflammatory response genes.
This precursor molecule could be targeted by atherosclerosis drugs, according to the study published in the Cell medical journal.
In our arterial walls are immune system cells called macrophages (which means "big eater" in Greek) that consume other cells or matter that are believed to be foreign or dangerous.
Senior author Christopher Glass, MD, PhD, a professor in the Departments of Medicine and Cellular and Molecular Medicine and senior author says, "When they do that, it means they consume the other cell's store of cholesterol. As a result, they've developed very effective ways to metabolize the excess cholesterol and get rid of it."
Some macrophages do not adequately dispose of the excess cholesterol and allow it to build up as foamy lipid (fat) droplets, hence their name, macrophage foam cells.
These foam macrophages generate molecules that call other immune cells and release molecules, signalling some genes to launch an inflammatory response. It assumed that atherosclerotic lesions - areas of fat-laden foam cells in arterial walls - are caused by a link between unregulated cholesterol accumulation and inflammation, says Christopher Glass.
The researchers set out to discover how cholesterol accumulation causes inflammation, and why macrophages perform. Using modelling based on mice that produce many macrophage foam cells, they had two unexpected discoveries.
"The first is that foam cell formation suppressed activation of genes that promote inflammation. That's exactly the opposite of what we thought happened. Second, we identified a molecule that helps normal macrophages manage cholesterol balance. When it's in abundance, it turns on cellular pathways to get rid of cholesterol and turns off pathways for producing more cholesterol."
That molecule is desmosterol - the last forerunner in cholesterol production, which cells create and use as a structural component of their membranes. In atherosclerotic lesions, the ordinary function of desmosterol seems to be "crippled."
The next area of research is to discover why that happens, says Christopher Glass. It may be connected to overwhelming, pro-inflammatory signals from proteins called Toll-like receptors on macrophages and other cells that are vital parts of the immune system.
Discovering desmosterol's ability to cut macrophage cholesterol gives researchers and drug developers a new target to cut the risk of atherosclerosis.
Christopher Glass says a synthetic molecule much the same as desmosterol already exists, which offers an immediate test-case for new studies.
Scientists in the 1950s developed a drug called triparanol that reduces cholesterol production, effectively boosting desmosterol levels. It was sold as a heart disease drug, but was later found to cause severe side effects, including blindness, so it was abandoned.
"We've learned a lot in 50 years. Maybe there's a way now to create a new drug that mimics the cholesterol inhibition without the side effects," concludes Christopher Glass.
The study's co-authors are: first author Nathanael J. Spann, Norihito Shibata, Donna Reichart, Jesse N. Fox and Daniel Heudobler, UCSD Department of Cellular and Molecular Medicine; Lana X. Garmire, UCSD Department of Bioengineering; Jeffrey G. McDonald and David W. Russell, Department of Molecular Genetics, UT Southwestern Medical Center; David S. Myers, Stephen B. Milne and Alex Brown, Department of Pharmacology, Vanderbilt Institute of Chemical Biology; Iftach Shaked and Klaus Ley, La Jolla Institute of Allergy and Immunology; Christian R.H. Raetz, Department of Biochemistry, Duke University School of Medicine; Elaine W. Wang, Samuel L. Kelly, M. Cameron Sullards and Alfred H. Merrill, Jr., Schools of Biology, Chemistry and Biochemistry and the Parker H. Petit Institute of Bioengineering and Bioscience, George Institute of Technology; Edward A. Dennis, UCSD Department of Chemistry and Biochemistry; Andrew C. Li, Sotirios Tsimikas and Oswald Quehenberger, UCSD Department of Medicine; Eoin Fahy, UCSD Department of Bioengineering; and Shankar Subramaniam, UCSD Departments of Cellular and Molecular Medicine, Bioengineering and Chemistry and Biochemistry.
Finance for the study was provided by various National Institutes of Health grants.