A biological ‘good guy’ has a dark side
A pair of Oklahoma Medical Research Foundation scientists have discovered
that an enzyme previously thought only to be beneficial could, in fact, pose
significant danger to developing embryos. The new research could have
implications not only for prenatal development but also for treating lymphedema
and liver damage resulting from acetaminophen overdose.
Using genetically engineered mouse embryos, OMRF’s Courtney Griffin, and Patrick
Crosswhite, looked at what would happen if they removed a protein that
determines how genes get turned on and off during blood vessel development. The
scientists found a marked increase in the activity of plasmin, an enzyme that is
known to help break up blood clots and promote blood vessel development. But in
a developing embryo, said Griffin, too much of the enzyme can pose a threat.
“Plasmin has always been seen in a positive light, but we’re not finding any
beneficial aspects of it in early development,” said Griffin. “In fact,
excessive plasmin does dangerous things in a growing embryo.”
The OMRF researchers also found that liver damage could ensue in embryos when
the protein that suppresses plasmin activity - known as CHD4 - was absent.
Too much plasmin makes liver blood vessels fragile and prone to bleeding. They
also found that excess plasmin could be harmful to the lymph system, an
essential part of the immune system, by breaking down blood clots that help the
lymphatic system function properly.
With this new information, Griffin and Crosswhite will study plasmin behavior
later in gestation and in adults. They’ll investigate how high concentration of
plasmin may contribute to conditions such as lymphedema, a painful lymph
disorder marked by swelling in the arms and legs. They’ll also look at whether
CHD4 continues protecting liver blood vessels from plasmin damage after birth.
More research is needed, said Griffin, but the findings may lead to clinical use
of plasmin-blocking compounds after acetaminophen overdose. Acetaminophen is the
active ingredient in Tylenol, and overdose is a leading cause of liver damage in
the U.S., resulting in up to 70,000 hospitalisations a year. “Excessive plasmin
activity in the liver has been linked to acetaminophen overdose,” said
Crosswhite, “and we suspect this plasmin may make liver blood vessels
dangerously weak.”
“This work is innovative and creative, from the results to the interpretation
and conclusions,” said Rodger McEver, chair of OMRF’s Cardiovascular Biology
Research Program.
“These scientists were able to show that plasmin is really important in ways
that hadn’t been discovered before. It gives us new information and is great
basic science, but the data could be clinically relevant to treating
acetaminophen toxicity in humans.”
- MNT
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