How a genetic mutation can cause individuals with normal cholesterol
levels to develop coronary artery disease at a young age

Date:
July 7, 2023
Source:
University of Texas Health Science Center at Houston
Summary:
A novel molecular pathway to explain how a mutation in the gene
ACTA2 can cause individuals in their 30s -- with normal cholesterol
levels and no other risk factors -- to develop coronary artery
disease has now been identified,.


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A novel molecular pathway to explain how a mutation in the gene ACTA2
can cause individuals in their 30s -- with normal cholesterol levels
and no other risk factors -- to develop coronary artery disease has been identified, according to researchers with UTHealth Houston.

The study was published in the European Heart Journal.

"The gene ACTA2 codes a specific protein that has nothing to do with cholesterol," said Dianna Milewicz, MD, PhD, senior author of the study
and professor and director of the Division of Medical Genetics at McGovern Medical School at UTHealth Houston. "It was a surprise to find that
people with the gene mutation had too much atherosclerosis at a young
age and with no risk factors." A 2009 study led by Milewicz found that
a number of mutations in ACTA2 predispose humans to develop early onset
(30s or younger) coronary artery disease.

Atherosclerosis is a buildup of fats, cholesterol, and other substances
in and on the artery walls. It can develop over time and most people don't
know they have it until they suffer a heart attack or stroke. Traditional
risk factors for developing atherosclerosis include high cholesterol,
high blood pressure, diabetes, smoking, obesity, lack of exercise,
and consuming a high-fat diet.

ACTA2 is typically found in the smooth muscle cells, which line the
arteries and allow the arteries to contract to control blood pressure
and flow. Milewicz and her team found that protein coded by this gene
is not folded correctly because of the mutation, and it triggers stress
in the smooth muscle cell, which then forces the cell to make more
cholesterol internally, regardless of the levels of cholesterol in the
blood, driving atherosclerotic plaque formation.

"This finding is unique in that we found a completely new pathway to atherosclerosis. It explains why for years we have known statins protect
people from heart attacks, even those people whose blood cholesterol
levels are normal. In the people with ACTA2 mutations, the statins block
the cholesterol made by the stressed smooth muscle cells," said Milewicz,
the President George Bush Chair in Cardiovascular Medicine with McGovern Medical School. "In our study, the mutant protein made by the ACTA2
mutation caused the cells in the artery wall to be stressed, but there
are many other factors that can stress cells. We are now working on the
risk factors for coronary artery disease, like hypertension, that would
also stress the cells and activate this novel pathway for coronary artery disease." One of the results of stress in smooth muscle cells associated
with atherosclerosis is the deposition of calcium in the arteries.

"Cardiac calcium imaging in individuals with ACTA2 mutations could be
a useful early diagnostic tool to monitor the development of the early atherosclerosis in these people. This would allow physicians to decide
at what age to start these patients on statins," Milewicz said.

Using a genetically engineered mouse that contains a particular
ACTA2 mutation and feeding the mice a diet rich in cholesterol, the
researchers induced atherosclerosis and found that these mice have
much more atherosclerosis than similarly treated mice normal mice. The
study also found that the increased atherosclerosis could be reversed
by treating the mice with pravastatin, a member of the statin group of
drugs commonly prescribed to lower blood cholesterol. The researchers
confirmed that same molecular pathway is activated in smooth muscles
cells isolated from a human patient with an ACTA2 mutation.

Statins prevent coronary artery disease by lowering the levels of
cholesterol in the blood. At the same time, more than half of heart
attacks occur in apparently healthy men and women with average or low
levels of plasma LDL- cholesterol. Statins also reduce heart attack
events in people with normal cholesterol levels.

This work was supported by the National Heart, Lung, and Blood
Institute (RO1 HL146583); an America Heart Association Merit Award,
NIH T32GM120011; Marfan Foundation McKusick Fellowship Award; and
American Heart Association Grant 20CDA35310689. Lipid profile analysis
was performed at the Mouse Metabolism and Phenotypic Core at Baylor
College of Medicine, funded by NIH RO1DK114356 and UM1HG006348. Single
cell RNA sequencing was performed at the Single Cell Genomics Core at
Baylor College of Medicine, funded by National Institutes of Health
shared instrument grants S10OD023469, S10OD025240 and P30EY002520.

Additional UTHealth Houston authors include Kaveeta Kaw, MD, PhD; Abhijnan Chattopadhyay, PhD; Pujun Guan, MM; Jiyuan Chen, PhD; Suravi Majumder,
PhD; Xue-yan Duan, PhD, and Callie S. Kwartler, PhD. Other authors
include Shuangtao Ma, MD, MSc, with Michigan State University College
of Human Medicine (a former postdoctoral fellow at UTHealth Houston)
and Chen Zhang, MD, with Baylor College of Medicine.

* RELATED_TOPICS
o Health_&_Medicine
# Heart_Disease # Cholesterol # Stroke_Prevention #
Diseases_and_Conditions # Hypertension # Triglycerides #
Diet_and_Weight_Loss # Genes
* RELATED_TERMS
o Ischaemic_heart_disease o Coronary_heart_disease o
Cholesterol o Low_density_lipoprotein o Huntington's_disease
o Erectile_dysfunction o Tumor_suppressor_gene o Trans_fat

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Original written by Jeannette Sanchez. Note: Content may be edited for
style and length.


========================================================================== Journal Reference:
1. Kaveeta Kaw, Abhijnan Chattopadhyay, Pujun Guan, Jiyuan Chen, Suravi
Majumder, Xue-yan Duan, Shuangtao Ma, Chen Zhang, Callie S Kwartler,
Dianna M Milewicz. Smooth muscle a-actin missense variant promotes
atherosclerosis through modulation of intracellular cholesterol
in smooth muscle cells. European Heart Journal, 2023; DOI:
10.1093/eurheartj/ ehad373 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2023/07/230707124650.htm

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