Sci. Aging Knowl. Environ., 28 January 2004
Hampering a Heartbreaker
Antibiotic might stem injury from heart attack
A TV ad urges people who think they're having a heart attack to pop an aspirin before rushing to the emergency room. They might be even better off taking antibiotics, according to a new study. The work shows that an antibiotic stems a previously untreatable form of heart damage not by killing bugs but by suppressing cellular enzymes.
Heart attacks inflict a double whammy. Starved of oxygen, heart cells die. If doctors act quickly, they can open obstructed blood vessels with a catheter or clot-busting drugs. But the organ continues to deteriorate after reperfusion, the restoration of blood flow, mainly because of a flood of ruinous reactive oxygen species (ROS). Many researchers contend that reperfusion itself unleashes the toxins. However, other cardiologists argue that the circulation shutdown triggers a chain of cell-destroying events that progresses despite reperfusion. In 2001, biochemist Roberta Gottlieb of the Scripps Research Institute in La Jolla, California, and colleagues restricted and then reinstated circulation in rabbit hearts and found that the antibiotic chloramphenicol forestalled damage. They wanted to find out how the drug works and whether it hinders heart deterioration after reperfusion.
The researchers surgically removed rat hearts, denied them oxygen for 30 minutes to simulate a heart attack, and then restored the supply. Hearts bathed with chloramphenicol throughout the experiment had less than one-half as much scarring as did untreated hearts. Adding chloramphenicol at the start of reperfusion provided the same benefit, suggesting that the majority of heart injury occurs after blood flow resumes, says Gottlieb. The researchers also found that the antibiotic cut production of the ROS superoxide.
Chloramphenicol hinders protein production in a cell's cytoplasm, and the researchers reasoned that it could do the same in mitochondria, where most ROS are made. They suspected that it might spare heart tissue by slowing mitochondrial metabolism, thus reducing ROS release. However, the team measured no reduction in mitochondrial protein activity in heart tissue soaked in the antibiotic. Chloramphenicol also inhibits cellular proteins called cytochrome P450 monooxygenases (CYPs), at least one of which spurs ROS production. The antibiotic lowered CYP activity in heart tissue, tests showed. Two other drugs that inhibit CYPs but don't alter mitochondrial protein production also reduced the amount of injured tissue. Together, the results suggest that CYPs promote tissue damage following reperfusion and that compounds that handcuff the proteins might spare heart cells, says Gottlieb. She expects clinical trials of such agents to begin within 2 years.
Most patients don't get to the emergency room until several hours after their heart attacks begin, so showing that a drug can save heart tissue after reperfusion commences is important, says physiologist Robert Lasley of the University of Kentucky, Lexington. "I think it's an excellent paper," says Terry Vanden Hoek, an emergency medicine doctor who studies reperfusion at the University of Chicago. Previous studies identified heart-protecting compounds, but they had to be given before an attack and wouldn't benefit patients "unless you put them in the drinking water," he says. Future work might show whether cardiologists should keep antibiotics handy along with stents and angioplasty balloons.
January 28, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150