Hibernation stress response decreases stroke brain damage in mice

Hibernation stress response decreases stroke brain damage in mice
American Stroke Association Meeting Report: Abstract LB8

This abstract is featured in a news conference.
Video interview clips available at embargo at ISC 2011 Multimedia: AHA/ASA Multimedia Resources Library.

Study Highlights:


•Inducing a hibernation-related cellular process that helps cells remain stable under stress significantly reduced the size of stroke-induced brain damage in animal testing.
•The hibernation process may lead to stroke therapy.


LOS ANGELES, Feb.11, 2011 — Inducing a natural cellular process that protects an animal’s body during hibernation significantly decreased the size of stroke-induced brain tissue damage in laboratory mice, according to late-breaking science presented at the American Stroke Association’s International Stroke Conference 2011.

In hibernation and stroke, blood and oxygen flow decrease drastically. Stroke can cause devastating tissue damage and death. However, hibernation is harmless, in part due to a complex process that occurs within the body’s cells to help them remain stable under stress.

The process, known as SUMOylation, occurs when a small protein called SUMO (Small Ubiquitin-like MOdifier) attaches to other proteins, altering their cellular functions. SUMOylation can modify a protein’s function in many ways, including making it resistant to environmental stressors like the low oxygen levels that occur during hibernation.

“We think this is one of the mechanisms related to making animals very tolerant to severe conditions,” said Yang-ja Lee, Ph.D., lead investigator and staff scientist at the National Institute of Neurological Disorders and Stroke in Bethesda, Md.

The protein Ubc9 is essential to activate the SUMOylation process, so researchers genetically-engineered mice to express Ubc9 throughout their bodies. They found that the size of induced brain tissue damage in the mice significantly decreased as levels of global SUMOylation increased. When they tripled the global SUMOylation level, brain tissue damage decreased by nearly 50 percent.

The size of brain damage decreased approximately from 32 cubic millimeters in controls to:


•25 cubic millimeters when SUMOylation doubled;
•17 cubic millimeters when SUMOylation tripled; and
•10 cubic millimeters when SUMOylation quadrupled.

Investigators found that increasing Ubc9 by three to five times the normal level significantly reduced the size of induced brain tissue damage to an average of about 19 cubic millimeters, compared with about 28 cubic millimeters in unaltered control mice. Increasing Ubc9 by more than five times had no further benefit, Lee said.

In previous studies, Lee and her research team demonstrated that hibernating ground squirrels displayed massive increases of SUMOyladtion in all tissues, not just in the brain. Subsequently, they showed that increasing Ubc9 levels in cultured cells in the laboratory protected against the extremely low availability of oxygen and glucose that occurs during hibernation and, under normal circumstances, would cause severe cellular damage.

This latest project takes the earlier findings a step further by demonstrating that SUMOylation and its protective effects can be increased in a living animal. Basic research like this is the critical first step in developing new therapies for stroke, Lee said.

“We thought that we could learn from nature and find a mechanism by which animals modify stress responses to survive severe conditions like stroke,” she said. “We wish we could increase the global SUMOylation even higher, but over-expressing Ubc9 alone didn’t make it go as high as it does in hibernators, as we had hoped. We have to find some other way to increase it more, and then we could see even greater protection.”

In the United States, stroke occurs in nearly 800,000 people and causes more than 137,000 deaths each year, according to the American Stroke Association.

Co-authors are: Yongshan Mou, M.D.; Dace Klimanis, M.S.; and John M. Hallenbeck, M.D.

Author disclosures are on the abstract.

The National Institute of Neurological Disorders and Stroke funded the research.

Statements and conclusions of study authors that are presented at American Heart Association scientific meetings are solely those of the study authors and do not necessarily reflect association policy or position. The association makes no representation or warranty as to their accuracy or reliability. The association receives funding primarily from individuals; foundations and corporations (including pharmaceutical, device manufacturers and other companies) also make donations and fund specific association programs and events. The association has strict policies to prevent these relationships from influencing science content. Revenues from pharmaceutical and device corporations are available at www.heart.org/corporatefunding.

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NR11-1020 (ISC 2011/ Lee)

(Note: Actual presentation time is 11:30 a.m. PT/2:30 p.m. ET, Friday, Feb. 11, 2011)


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Hibernation stress response decreases stroke brain damage in mice