Researchers learn how ‘bad cholesterol’ enters artery walls in condition linked to world’s No. 1 killer

UT Southwestern Medical Center

DALLAS –
April 25, 2019 – UT Southwestern researchers have determined how
circulating “bad cholesterol” enters artery walls to cause the plaque
that narrows the blood vessels and leads to heart attacks and strokes.

Since
low-density lipoprotein, or LDL, cholesterol entry into the artery wall drives
the development of atherosclerosis, or hardening of the arteries, and
atherosclerosis leads to heart attacks and strokes, future treatments
preventing the process may help decrease the occurrence of these life-threatening
conditions, said Dr. Philip Shaul, senior author of the study published online
today in Nature.

Cardiovascular
disease
is the No. 1
cause of death worldwide, and coronary artery disease (which underlies
heart attacks) and strokes account for over 60% of cardiovascular deaths in the
U.S., according to recent statistics from the American Heart Association (AHA).

The study
reveals for the first time how a protein called SR-B1 (short for
scavenger receptor class B, type 1) ferries LDL particles into and then across
the endothelial cells that line arteries. The study also found that a second
protein called dedicator of cytokinesis 4, or DOCK4, partners with SR-B1
and is necessary for the process.

In the early
stages of atherosclerosis, LDL that has entered the artery wall attracts
and is engulfed by important immune system cells called macrophages that
ingest, or “eat,” LDL particles. LDL-laden macrophages become foam cells that
promote inflammation and further the development of atherosclerotic plaques.

The plaques
narrow the artery and can become unstable. Plaques that rupture can activate
blood clotting and block blood flow to the brain or heart, resulting in a
stroke or heart attack. In studies of mice with elevated cholesterol, the
investigators determined that deleting SR-B1 from the endothelial cells lining
blood vessels resulted in far less LDL entering the artery wall, fewer foam
cells formed, and atherosclerotic plaques that were considerably smaller.

“At the
start of this work it was surprisingly unknown how LDL enters the artery wall
to cause cardiovascular disease,” said Dr. Shaul, Director of the Center for
Pulmonary and Vascular Biology at UT Southwestern. “The paper’s findings solve
that mystery and counter many scientists’ prior assumption that LDL simply
enters through sites of damage or disruption in the single layer of endothelial
cells that serves as the artery wall’s protective barrier.”

In their
studies, the researchers compared SR-B1 and DOCK4 abundance in areas of the
mouse aorta that are prone to plaque formation compared with regions less
likely to become atherosclerotic. They found higher levels of SR-B1 and DOCK4
in the disease-prone regions long before atherosclerotic plaques formed. This
finding suggests that atherosclerotic lesions may be more common in particular
artery sites because of more SR-B1 and DOCK4 present there, said Dr. Shaul,
UTSW Vice Chair of Research and Professor of Pediatrics, who holds the
Associates First Capital Corporation Distinguished Chair in Pediatrics.

To determine
if these findings might apply to people, the researchers reviewed data on
atherosclerotic and normal arteries from humans in three independent databases
maintained by the National Institutes of Health (NIH). In all three databases,
SR-B1 and DOCK4 were more abundant in atherosclerotic arteries compared with
normal arteries.

The
researchers are now exploring the possibility of using gene therapy to turn off
or reduce the function of SR-B1 or DOCK4 in the endothelial cells that line arteries
in order to prevent atherosclerosis, Dr. Shaul said.

“If you
could develop a drug that inhibits SR-B1 or DOCK4, or a gene therapy that
silences them in endothelial cells, you could potentially decrease
atherosclerosis and, hence, reduce the incidence of coronary artery disease,
heart attack, and stroke,” he said. “Such strategies would complement current
treatments that lower circulating LDL and be particularly valuable in
situations in which LDL lowering is challenging.”

Dr. Chieko
Mineo, Associate Professor of Pediatrics and Cell Biology, directed the project
with Dr. Shaul, and Dr. Linzhang Huang, a postdoctoral researcher, was first
author of the study. Co-authors include researchers at the Children’s Medical
Center Research Institute at UT Southwestern, New York University School of
Medicine, and Cornell University.

The study received support from the NIH, the AHA, the Henrietta B. and Frederick H. Bugher Foundation, the Rally Foundation for Childhood Cancer Research, and The Children’s Cancer Foundation Inc.

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