Sci. Aging Knowl. Environ., 22 October 2003
Quench a Burning Heart
Cardiac protein stanches inflammation and stymies heart failure
Key Words: cardiac fibrosis cardiomyocytes apoptosis
Like a flame slowly burning through a piece of wood, inflammation gnaws at the heart, sapping its pumping power. A new study suggests that a protective protein fashioned by the heart works by quashing an inflammation-sparking molecule. The finding could guide researchers to treatments that prevent heart failure, the number one cardiac killer among the elderly.
Although the death rate from heart attacks has plummeted since the 1960s, more patients over age 65 are suffering from heart failure, the progressive weakening of the organ. Several lines of evidence implicate inflammation in heart failure. For example, researchers have discerned an overabundance of certain immune-stimulating compounds in heart failure patients. A 2001 study found that people with faltering hearts were more likely to die if they showed an excess of a molecule called IL-6. However, IL-6 might not be all bad. It can cool as well as spark inflammation by rousing other proteins, and many researchers think that the surge in IL-6 indicates that the body is trying to curtail heart damage. Research on STAT3, a molecule indirectly activated by IL-6, supports that view. The heart exudes STAT3 in response to oxygen scarcity, heart attack, or other stresses. Three years ago, Japanese researchers showed that genetically altering mice to make extra STAT3 shields their hearts against damage from an oxidant called doxorubicin. Kerry Russell of Yale University School of Medicine in New Haven, Connecticut, and colleagues wanted to find out more about how this molecule protects cardiac cells.
Because mice that lack the STAT3 gene die before birth, the team disabled it only in heart muscle cells. The researchers first confirmed that animals without STAT3 are more vulnerable to doxorubicin. Then they injected altered and control mice with a different compound that incites inflammation; nearly four times as many heart cells perished in the altered animals. Repeating the experiment on heart cells in a culture dish, the team found that cells lacking STAT3 oozed about five times as much tumor necrosis factor (TNF), another molecule that promotes inflammation. Even without prodding with harsh chemicals, the hearts of mice without STAT3 accumulated scar tissue and weakened faster than normal as the animals aged. The researchers measured how much the heart muscle contracts--a gauge of its strength--with echocardiograms, sonograms of the heart. Among mice more than 200 days old, the heart contracted only one-third as much in STAT3-lacking mice as it did in unaltered controls.
Previous work implied that STAT3 guards heart cells, and these results suggest it does so by squelching TNF and thus dampening inflammation, says cardiologist Douglas Mann of Baylor College of Medicine in Houston, Texas. Tweaking this soothing pathway potentially "offers a way of using nature's own method of suppressing inflammation," he says. "It's a very elegant study," says cardiologist Barry Greenberg of the University of California, San Diego. However, he wants further work to determine whether the heart-guarding protein activates other protective mechanisms--enlarging cells, for instance. Coaxing STAT3 into action might douse inflammation and save the heart from burning up.
October 22, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150