January 26, 2004
The Body’s 911 Call: Why Blood Flow Stops Short
Penn researchers find that oxidation of Cysteine911
leads to restricted blood flow
(Philadelphia, PA) – While it’s common knowledge
that high levels of LDL, also known as “bad”
cholesterol, can lead to the restriction of blood vessels
and a higher incidence of heart attack, stroke and diabetes,
the exact method of “how” has remained a
mystery. Now, researchers from the University
of Pennsylvania School of Medicine have discovered
the exact mechanism to explain why blood vessels are
restricted in patients with cardiovascular diseases,
thus preventing blood flow and causing disease symptoms.
These finds will be published in the February issue
of Nature Structural and Molecular Biology.
“We all have oxygen-heavy toxins in our bodies,”
said scientist Xiang Dong Tang, MD, PhD
of Penn’s Department of Physiology. “When
there are high levels of LDL or sugars in the blood,
those toxins are generated in excess, and the body can’t
break them down as efficiently as a healthy body can.
This kicks off a chain reaction that leaves blood vessels
contracted. Now we know how that chain works, down to
the amino acid residue that is targeted.”
That amino acid is Cysteine at position 911 of a protein
called the Maxi-K potassium channel, which is typically
made of approximately 1,200 amino acids. The Maxi-K
channel moves potassium ions out of blood vessel muscles
and serves as a critical regulator for blood vessel
tone. It works in one of two ways: either from an electric
shock or an increase in calcium within the channel.
When Cysteine911 is altered by an oxygen-heavy toxin,
calcium doesn’t enter the Maxi-K channel. If the
Maxi-K channel is inhibited, then the vascular muscle
isn’t told to relax, thus restricting blood flow.
“We also found that the Maxi-K channel isn’t
permanently damaged when Cysteine911 is altered,”
said Toshinori Hoshi, PhD, Associate
Professor in Penn’s Department of Physiology and
co-author of the article. “In fact, with the right
chemical agent, it can be reversed.” In initial
laboratory tests, the researchers have found that a
chemical, NS1619, can allow the damaged Maxi-K channel
to continue to function.
“This discovery could lead to the production of
drugs that would reverse the negative effects on the
Maxi-K channel. It would be an alternative method for
treating cardiovascular diseases and even diseases relating
to aging,” said Hoshi.
“According to estimates by the American Heart
Association, cardiovascular diseases and stroke will
cost the United States $368 billion in 2004,”
said Tang. “Obviously, not enough people are lowering
their cholesterol through traditional methods such as
a low-cholesterol diet or quitting smoking, so we are
seeking alternative, biological methods of treatment.
These findings are a major step in that direction.”
Scientists also contributing to this research include
Marcia L. Garcia from Merck Research Institution and
Stefan H. Heinemann from Friedrich Schiller University.
This research is funded by the National Institutes of
This study can be found online at http://www.nature.com/cgi-taf/DynaPage.taf?file=nsmb/journal/vaop/ncurrent/index.html
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