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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 Health.

This study can be found online at http://www.nature.com/cgitaf/DynaPage.taf?file=nsmb/journal/vaop/ncurrent/index.html

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PENN Medicine is a $2.2 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System (created in 1993 as the nation’s first integrated academic health system).

Penn’s School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report’s most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

Penn Health System consists of four hospitals (including its flagship Hospital of the University of Pennsylvania, consistently rated one of the nation’s “Honor Roll” hospitals by U.S. News & World Report), a faculty practice plan, a primary-care provider network, three multispecialty satellite facilities, and home health care and hospice.

Release available online at http://www.uphs.upenn.edu/news/News_Releases/jan04/911call.htm