How the body regulates scar tissue growth after heart attacks
A single protein may determine how much scarring occurs

Date:
July 6, 2020
Source:
University of California - Los Angeles Health Sciences
Summary:
New research conducted in mice could explain why some people suffer
more extensive scarring than others after a heart attack. The study
reveals that a protein known as type 5 collagen plays a critical
role in regulating the size of scar tissue in the heart.



FULL STORY ==========================================================================
New UCLA research conducted in mice could explain why some people suffer
more extensive scarring than others after a heart attack. The study,
published in the journal Cell, reveals that a protein known as type 5
collagen plays a critical role in regulating the size of scar tissue in
the heart.


==========================================================================
Once formed, heart scar tissue remains for life, reducing the heart's
ability to pump blood and adding strain to the remaining heart
muscle. People who develop larger scars have a higher risk of heart
rhythm problems, heart failure and sudden cardiac death.

"Two individuals with the same degree of heart attack can end up with
different amounts of scar tissue," said Dr. Arjun Deb, the study's senior author and a member of Eli and Edythe Broad Center of Regenerative
Medicine and Stem Cell Research at UCLA. "Given the clear correlation
between scar size and survival rates, we set out to understand why some
hearts scar more than others. If we can reduce this scarring, we can
greatly improve survival." Following a heart attack, connective tissue
cells called fibroblasts secrete a variety of proteins that combine to
form scar tissue. The vast majority of these proteins are collagens,
of which there are 26 types, all functioning as a kind of glue that
holds the body together.

Type 1 and 3 collagens are abundant in the uninjured heart and also
make up about 97% of scar tissue. Interestingly, Deb's team observed
that several collagens not found in the uninjured heart were abundant
in scar tissue. Among this group, type 5 collagen stood out.

To determine the role this collagen plays in scarring, the researchers genetically engineered a mouse model that was incapable of producing
type 5 collagen in scar tissue following a heart injury. The results
were surprising.



========================================================================== "Normally if you delete a collagen, you would expect the scar tissue size
to decrease because collagen forms scar tissue. We found, paradoxically,
that the scar size actually increased by 50%," said Deb, who is a
professor of medicine in the division of cardiology at the David Geffen
School of Medicine at UCLA and director of the school's cardiovascular
medicine research theme.

Digging deeper, Deb and his collaborators from the Geffen School of
Medicine, the California NanoSystems Institute at UCLA and the UCLA
Division of Life Sciences found that type 5 collagen was regulating the stiffness of scar tissue. Without it, the scar tissue was less stiff and therefore prone to expansion from the force of the blood within the heart.

"Scar tissue without type 5 collagen is compliant like rubber," Deb
said. "So when the heart fills with blood, the scar tissue expands in much
the same way as a rubber balloon expands when it is filled with air."
This expansion, the team observed, was only the beginning. The protein- secreting fibroblasts are alerted to the scar's expansion by their
integrins, receptors found within the cell membrane that sense changes
to the environment and send signals inward to adjust how the cell is
behaving in response to these changes. The fibroblasts consequently
secrete more proteins in an attempt to reinforce the scar and stop the expansion. But without type 5 collagen, Deb noted, the cycle of expansion
and scar growth simply continues.

To stop the cycle, Deb tested a drug called Cilengitide that disrupts
integrin signaling. Developed as a cancer treatment, the drug was found to
be safe for use in humans in a phase 3 clinical trial. The team found that treating the type 5 collagen-deficient mice with Cilengitide disrupted
this feedback cycle and reduced scar size.

Subtle expression differences in type 5 collagen could explain why some
heart attack survivors form larger scars than others, said Deb, who is
also a professor of molecular, cell and developmental biology.

He is now working to develop a test that would identify people whose
bodies produce less type 5 collagen. It is possible that such a test
could one day be used in a precision medicine approach aimed at people
who may be prone to increased scarring from heart attacks and could
benefit from drugs such as Cilengitide.

Deb's team is also collaborating with physicians and scientists from
the division of dermatology at the Geffen School of Medicine to pursue a potential immediate clinical application for people with Ehlers-Danlos syndrome, a connective tissue disorder characterized by excessive
scarring, even from minor injuries, due to mutations in the gene that
produces type 5 collagen.

The use of Cilengitide has not been tested in humans as a treatment
for excessive scarring and has not been approved by the Food and Drug Administration as safe and effective for this use. The newly identified
method for treating dysregulated wound healing is covered by a patent application filed by the UCLA Technology Development Group on behalf of
the Regents of the University of California.


========================================================================== Story Source: Materials provided by University_of_California_-_Los_Angeles_Health_Sciences.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Tomohiro Yokota, Jackie McCourt, Feiyang Ma, Shuxun Ren, Shen
Li, Tae-
Hyung Kim, Yerbol Z. Kurmangaliyev, Rohollah Nasiri, Samad Ahadian,
Thang Nguyen, Xing Haw Marvin Tan, Yonggang Zhou, Rimao Wu, Abraham
Rodriguez, Whitaker Cohn, Yibin Wang, Julian Whitelegge, Sergey
Ryazantsev, Ali Khademhosseini, Michael A. Teitell, Pei-Yu Chiou,
David E. Birk, Amy C.

Rowat, Rachelle H. Crosbie, Matteo Pellegrini, Marcus Seldin,
Aldons J.

Lusis, Arjun Deb. Type V Collagen in Scar Tissue Regulates
the Size of Scar after Heart Injury. Cell, 2020; DOI:
10.1016/j.cell.2020.06.030 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2020/07/200706100815.htm

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