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Researchers at the University of Colorado School of Medicine have discovered a new mechanism that slows scarring of heart tissue, a process known as cardiac fibrosis
.
"Cardiac fibrosis is a response to various stresses," said
Dr.
Timothy McKinsey, a professor of medicine in cardiology and corresponding author of the study.
"That's probably a good thing
.
For example, if you have a heart attack and a large amount of your heart muscle dies, you need to replace those muscles
with something else.
In this case, fibrotic scarring can prevent the heart from rupturing, preventing someone from dying
.
But we are more interested in pathological fibrosis, an uncontrolled fibrosis
that occurs in people with long-term high blood pressure or other comorbidities.
This can lead to hardening of the heart, leading to diastolic dysfunction
.
”
The CU study, published today in the American Heart Association's Journal of Circular Research, shows that compound SW033291 slows fibrosis by inhibiting the action of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme that degrades eicosanoids, lipid-signaling molecules
that help prevent fibrosis.
"Chronic fibrosis is thought to be a major factor
in the pathogenesis of heart failure," McKinsey said.
"Heart failure affects millions of people worldwide, and there is currently no good treatment to prevent or reverse heart fibrosis
.
That's why
we initiated these studies.
”
McKinsey and his research team began their research by using a phenotypic high-throughput screen using a number of compounds, looking to block the activation of fibroblasts, which are responsible for driving fibrosis
.
They stumbled upon 9 small molecules with the common ability
to block activation by fibroblasts in the heart, lungs and kidneys.
Of these 9 compounds, compound SW033291 seems to be the most promising
.
In addition to laboratory tests and animal models, CU researchers worked with Michael Bristow, M.
D.
, professor of cardiology, and Amrut Ambardekar, M.
D.
, associate professor of cardiology, and their team to create a new biobank
from patients who received heart transplants, as well as non-failed donor control heart fibroblasts.
SW033291 has demonstrated remarkable ability to reverse the activation state of failed human cardiac fibroblasts, McKinsey said, supporting the notion
that 15-PGDH inhibition may help improve existing cardiac fibrosis in patients.
As research continues, McKinsey and his team plan to focus on the role of 15-PGDH in different cell populations, including fibroblasts, immune cells, and cardiomyocytes
.
They also hope to conduct additional efficacy studies on SW033291 to test
in more severe models of cardiac fibrosis and diastolic dysfunction.
McKinsey said the team also plans to take a closer look at the function of different eicosanoids in inhibiting fibroblast activation and how they activate signaling pathways to prevent fibroblasts from causing fibrosis
.
"This study has identified a new pathway
to regulate cardiac fibrosis," he said.
"No one has studied 15-PGDH
in the heart.
This opens up a whole new avenue of research and proposes ways
to target cardiac fibrosis for the treatment of multiple heart diseases, including heart failure.
”
This work was supported in part by the Fibrosis Research and Translation Consortium, a project funded by the CU School of Medicine and co-directed
by McKinsey.
It aims to improve the understanding
of fibrotic diseases in different organ systems.
