Green tea molecule could prevent heart attacks
Scientists have discovered that a compound found in green tea, currently being studied for its ability to reduce amyloid plaques in the brain in Alzheimer’s disease, also breaks up and dissolves potentially dangerous protein plaques found in the blood vessels.
David Townsend, Eleri Hughes, Geoffrey Akien, Katie L. Stewart, Sheena E. Radford, David Rochester, David A. Middleton. Epigallocatechin-3-gallate remodels apolipoprotein A-I amyloid fibrils into soluble oligomers in the presence of heparin. Journal of Biological Chemistry, 2018; jbc.RA118.002038 DOI: 10.1074/jbc.RA118.002038
Engineering Evil Note: “Statins inhibit the action of HMGCoA reductase, the rate limiting enzyme of the cholesterol synthesis pathway. Plasma levels of markers of cholesterol synthesis (desmosterol, lathosterol) will be reduced by statins”
New way of fighting high cholesterol upends assumptions
|IMAGE:When macrophages take up massive amounts of cholesterol they form “foam cells,” characterized by multiple lipid droplets (stained red).|
Atherosclerosis – the hardening of arteries that is a primary cause of cardiovascular disease and death – has long been presumed to be the fateful consequence of complicated interactions between overabundant cholesterol and resulting inflammation in the heart and blood vessels.
However, researchers at the University of California, San Diego School of Medicine, with colleagues at institutions across the country, say the relationship is not exactly what it appears, and that a precursor to cholesterol actually suppresses inflammatory response genes. This precursor molecule could provide a new target for drugs designed to treat atherosclerosis, which kills tens of thousands of Americans annually.
The findings are published in the September 28, 2012 issue of Cell.
Lurking within our arterial walls are immune system cells called macrophages (Greek for “big eater”) whose essential function is to consume other cells or matter identified as foreign or dangerous. “When they do that, it means they consume the other cell’s store of cholesterol,” said Christopher Glass, MD, PhD, a professor in the Departments of Medicine and Cellular and Molecular Medicine and senior author of the Cell study. “As a result, they’ve developed very effective ways to metabolize the excess cholesterol and get rid of it.”
But some macrophages fail to properly dispose of the excess cholesterol, allowing it to instead accumulate inside them as foamy lipid (fat) droplets, which gives the cells their particular name: macrophage foam cells.
These foam macrophages produce molecules that summon other immune cells and release molecules, signaling certain genes to launch an inflammatory response. Glass said conventional wisdom has long assumed atherosclerotic lesions – clumps of fat-laden foam cells massed within arterial walls – were the unhealthy consequence of an escalating association between unregulated cholesterol accumulation and inflammation.
Glass and colleagues wanted to know exactly how cholesterol accumulation led to inflammation, and why the macrophages failed to do their job. Using specialized mouse models that produced abundant macrophage foam cells, they made two unexpected discoveries that upend previous assumptions about how lesions form and how atherosclerosis might be more effectively treated.
“The first is that foam cell formation suppressed activation of genes that promote inflammation. That’s exactly the opposite of what we thought happened,” said Glass. “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 final precursor in the production of cholesterol, which cells make and use as a structural component of their membranes. In atherosclerotic lesions, Glass said the normal function of desmosterol appears to be “crippled.”
“That’s the next thing to study; why that happens,” Glass said, hypothesizing that the cause may be linked to overwhelming, pro-inflammatory signals coming from proteins called Toll-like receptors on macrophages and other cells that, like macrophages, are critical elements of the immune system.
The identification of desmosterol’s ability to reduce macrophage cholesterol presents researchers and drug developers with a potential new target for reducing the risk of atherosclerosis.
Glass noted that a synthetic molecule similar to desmosterol already exists, offering an immediate test-case for new studies. In addition, scientists in the 1950s developed a drug called triparanol that inhibited cholesterol production, effectively boosting desmosterol levels. The drug was sold as a heart disease medication, but later discovered to cause severe side effects, including blindness from an unusual form of cataracts. It was pulled from the market and abandoned.
“We’ve learned a lot in 50 years,” said Glass. “Maybe there’s a way now to create a new drug that mimics the cholesterol inhibition without the side effects.”
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.
Funding for this research came, in part, from National Institutes of Health grants GM U54069338 (to the LIPID MAPS Consortium), P01 HC088093 and P01 DK074868.
Rogue bacteria involved in both heart disease and infertility
Researcher uncovers how chlamydia sabotages human immunity
Chlamydia pneumoniae is a microbe that normally causes pneumonia and bronchitis, but it has long been associated with atherosclerosis, a cardiovascular disease also called “hardening of the arteries.”
“It was a frightening prospect,” says Azenabor, “that atherosclerosis could come from a bacterial infection.” He decided to look for an explanation.
Chlamydiae are unusual, says the Nigerian-born scientist, because, unlike most other bacteria, they use the same form of cholesterol for metabolism that human cells use. Chlamydiae also are intracellular pathogens, meaning that they can only grow and reproduce inside of another cell.
But these bacteria have another peculiar ability.
Normally, when a pathogen invades human tissue, the immune response unleashes “killer cells” called macrophages, which stretch to engulf the attacker and destroy it with toxin-producing enzymes.
Chlamydiae fight back, says Azenabor, His work shows that, as they are ingested, these two species of Chlamydia can manipulate the functions of protective cells like macrophages in creative ways.
One of the keys lies in the macrophages’ cell walls, which store cholesterol and usually tightly control it.
But when it’s infected with C. pneumoniae, the microbe traffics cholesterol from the macrophage cell membrane to its own, causing a change in the macrophage that makes it rigid and unable to move.
The bacterium also disturbs the macrophage’s production of toxins in a process that transforms them into “signaling molecules,” which support functions that keep the bacterium alive.
“C. pneumoniae really wants to hijack the cell functions for its own use, like a parasite would,” he says. “The macrophage, though, wants to kill Chlamydia, but its killing ability has been converted to signaling.”
This is the reason the infection becomes chronic, Azenabor says. “Because of signaling, everything else in the human cell is still fine except for the altered toxins, so the bacteria can reproduce in a short time.”
As the macrophages become immobile, they accumulate in the blood vessel walls, setting the stage for atherosclerosis.
Infection and pregnancy
Armed with new information about how C. pneumoniae sabotages the immune response, Azenabor, who had also been studying the effects of estrogen on macrophages, turned his attention to another Chlamydia-related puzzle.
How is Chlamydia trachomatis, the species that causes a sexually transmitted disease, involved in the occurrence of spontaneous abortions or miscarriages?
He was immediately drawn to the protective cells in the placenta during early pregnancy – the trophoblasts.
“It’s not for nothing that trophoblasts are the early cells,” says Azenabor. “They prevent any kind of infection that could threaten the fertilized egg. They produce toxic chemicals similar to those of macrophages.”
Trophoblasts act like macrophages in many ways, and their functions are mediated by the hormones estrogen and progesterone. And cholesterol is the molecule used to produce those hormones.
Azenabor’s research shows that, like its cousin, C. trachomatis does take cholesterol from the trophoblast, and it also reproduces once inside the cell.
“It’s the same old story,” says Azenabor. “Only this time the attacked cell is a trophoblast instead of a macrophage, and the depleted cholesterol hinders production of estrogen and progesterone instead of altering toxin production.”
Azenabor’s lab members are continuing their inquiry, and they then will need to test the theories with live animals.
But the scientist is optimistic. Already he has a patented process for blocking the effects of calcium signaling for C. pneumoniae.
“If we can prevent C. trachomatis from becoming chronic, we could apply this remedy to pregnancy,” he says.
While conducting postdoctoral work at McMaster University in Ontario, he won the Canadian Distinguished Scientist Award in 1998, and moved to the University of Waterloo.
Azenabor joined the UWM faculty in 2001, after working as a scientist in a Chlamydia lab at UW–Madison. He jumped at the chance to start his own lab at UWM. Since arriving here he has won several honors, including the Shaw Distinguished Scientist Award from the James D. and Dorothy Shaw Fund in the Greater Milwaukee Foundation.
Although he didn’t plan on working with Chlamydia for this long, he is now a leading researcher in the field. One attraction, he says, is the work is unpredictable.
“When you begin,” he says, “you never know where you are going to go.”
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Environmental toxicants such as dioxins, PCBs, and pesticides can pose a risk for cardiovascular disease. For the first time a link has been demonstrated between atherosclerosis and levels of long-lived organic environmental toxicants in the blood. The study, carried out by researchers at Uppsala University, is being published online this week in ahead of print in the prestigious journal Environmental Health Perspectives.
Cardiovascular diseases, including heart attacks and strokes, are the most common cause of death in industrialized countries, and the most important underlying cause of these diseases is atherosclerosis. Unbalanced blood fats, diabetes, smoking, and high blood pressure are traditionally recognized risk factors for atherosclerosis.
Previous studies have also reported possible links between cardiovascular disease and high levels of persistent (long-lived and hard-to-degrade) organic environmental toxicants, such as dioxins, PCBs, and pesticides. These compounds are fat-soluble and can therefore accumulate in vessel walls. However, no earlier studies have investigated possible links between exposure to these compounds and atherosclerosis.
The current study measured the circulating levels of the above group of compounds in about 1,000 Swedes living in Uppsala. Atherosclerosis in the carotid artery was also measured using ultrasound.
The findings show a clear connection between increasing levels of environmental toxicants and atherosclerosis, even after taking into consideration the traditional risk factors. There was also a link to tangible signs of fat accumulation in vessel walls.
“These findings indicate that long-lived organic environmental toxicants may be involved in the occurrence of atherosclerosis and thereby lead to future death from cardiovascular diseases,” says Lars Lind, professor at the Department of Medical Sciences, Uppsala University.
“In Sweden, and in many countries in the world, many of these substances are forbidden today, but since they are so long-lived they’re still out there in our environment. We ingest these environmental toxicants with the food we eat, and since they are stored in our bodies, the levels grow higher the older we get,” says Monica Lind, Associate Professor in Environmental Medicine at Occupational and Environmental Medicine
These researchers are now going on to study how these compounds affect atherosclerosis in experimental models. They are also going to monitor the individuals included in their study to determine whether a direct connection exists between exposure to these substances and the occurrence of heart attacks and strokes in humans