This would seem to make much more sense than treating for cholesterol.
https://medicalxpress.com/news/2017-06-mechanism-shown-reverse-disease-arteries.html
A certain immune reaction is the key, not to
slowing atherosclerosis like cholesterol-lowering drugs do, but instead
to reversing a disease that gradually blocks arteries to cause heart
attacks and strokes.
This is the finding of a study in mice led by researchers at NYU Langone Medical Center and published online June 26 in the Journal of Clinical Investigation.
The study focuses on reversing the effects of "bad cholesterol,"
which is deposited into the walls lining blood vessels in levels
influenced by both genetics and a person's diet. By the fourth decade of
life, and thanks to the chronic reaction to cholesterol, most people
have inflamed "wounds" in their arteries called plaques, which when severe enough can rupture to cause blood clots that block arteries.
"Even the latest, most potent cholesterol-lowering drugs, PCSK9
inhibitors, let alone widely used statins, cannot fully reverse damage
done to arteries over time, and so they can't prevent roughly 500,000
heart attacks per year in the United States," says lead study author
Edward Fisher, MD, PhD, director of the Marc and Ruti Bell Vascular
Biology and Disease Program at NYU Langone.
"We need the next generation of drugs to go beyond cholesterol
lowering to address the immune reaction to accumulated cholesterol, and
to dismantle plaques as part of reversing or regressing mature disease,"
says Fisher, the Leon H. Charney Professor of Cardiovascular Medicine
at NYU Langone.
In years of painstaking research, the NYU Langone-led research team
has zeroed in on the molecular events that occur in arteries when
regression of atherosclerotic plaques is underway.
Once deposited into arteries, bad cholesterol
- known to physicians as low density lipoprotein - triggers the body's
immune system, which is meant to destroy invading microbes but can drive
inflammatory disease in the wrong context. Immune cells in the
bloodstream called monocytes swarm to cholesterol deposits, and become either inflammatory or healing cell types based on signals there.
In situations where disease is worsening in a plaque,
past studies have shown that monocytes become M1 macrophages that
amplify immune responses, increase inflammation, and secrete enzymes
that gnaw at plaques until they rupture. The current study confirmed
that monocytes arriving in plaques where disease is regressing instead
become M2 "healing" macrophages, which dampen inflammation and prevent
the ruptures that precede clotting.
When mice were engineered to lose the ability of monocytes to become
M2 macrophages, they could no longer achieve normal disease regression,
say the authors.
By surgically transplanting plaques from diseased mice into the
arteries of healthy mice, the research team brought about dramatic drops
in cholesterol levels. This drop has been shown to trigger a second
benefit in mice, where monocytes automatically become M2 instead of M1
macrophages as plaques rapidly regress.
It is not known whether cholesterol lowering alone triggers this M2
switch in humans. But new imaging techniques may soon be able to detect
changes in the type and number of macrophages in plaques. In the
meantime, if researchers learn how to boost the M2 switch, a number of
clinical applications may become possible just as methods arrive that
can measure their success.
"A race is underway to develop treatments that enhance the decision
of human monocytes to become M2 macrophages in cases where the disease
has not yet caused clot formation, at which point it becomes
irreversible," says Fisher.
Specifically, the current study found that the same blood-borne
Ly6Chigh monocytes, once thought of only as precursors to
"inflammation-prone" M1 macrophages, instead become anti-inflammatory M2
cells when they arrive in a regressing plaque. Having found the class
of cells from which M2 macrophages arise, the team is now seeking to
identify the local signals that tell monocytes to become M2.
Among the candidates are the immune signaling proteins interleukin-4
and interleukin-13, which have been linked by past studies to the M2
decision. These interleukins are known to turn on the STAT6 pathway,
which sends this protein to the nucleus where it turns on genes that
direct a monocyte to become a M2 macrophage. Researchers confirmed that
blocking the action of STAT6 reduced the number of M2 macrophages in
regressing plaques.
Fisher's team is already experimenting with nanoparticles based on
the structure of "good cholesterol," which is known to take cholesterol
of out of plaques and deliver it to the liver for destruction. One
version of their nanoparticle delivers interleukin 4 to plaques as well.
A next step for the work would be a study of nanoparticles in pigs, a
model where success can set the stage for human trials.
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