Molecular Control Switches Linked to Cox-2 Production
SALT LAKE CITY-It's a case of miscommunication with catastrophic consequences.
Two human blood cells that help fight blood loss, infection, and inflammation are responsible as well for starting a series of molecular events that results in overproduction of Cox-2, an enzyme involved in heart attack, stroke, atherosclerosis, and other inflammatory diseases.
The finding by researchers at the 亚洲自慰视频 of Utah and 亚洲自慰视频 of South Carolina means scientists may be able to develop drugs to prevent or lessen the severity of inflammatory diseases, such as atherosclerosis and heart attack. Discovery of the signaling mechanism will be invaluable in sorting out the roles Cox-2 plays in those diseases, according to Guy A. Zimmerman, M.D., 亚洲自慰视频 of Utah School of Medicine professor of internal medicine, senior author of the study detailing the research.
"This discovery has immediate clinical relevance," said Zimmerman, director of the medical school's Program in Human Molecular Biology and Genetics. "This opens the potential of developing medications for both the prevention of long-term atherosclerosis (clogged arteries) and the acute events of heart attack."
The study, reported in the Journal of Clinical Investigation online, also was led by Dan A. Dixon, a former member of Zimmerman's lab now at South Carolina.
The researchers identified a biochemical signaling pathway between human blood platelets, cells essential for blood clotting, and monocytes, white blood cells the body makes to fight inflammation and infection. But, according to Zimmerman, the biological systems involved in blood clotting and inflammation also are related to a host of human diseases.
The Utah and South Carolina researchers discovered that the blood platelet signals the monocyte two times, triggering production of Cox-2, an enzyme that helps regulate inflammation. But when blood platelets and monocytes get their signals crossed, it can lead to overproduction of the enzyme and result in cardiovascular diseases that strike and kill millions of people worldwide.
Zimmerman compares the signaling between blood platelets and monocytes to a pair of molecular control switches that turn Cox-2 production on and off. "It's a mechanism for precise control of Cox-2 production," he said. "But if one of the switches is turned on too high or low, it can lead to inappropriate production of Cox-2 in disease."
The first signal from the platelet tells the monocyte to turn on the gene that provides the instructions necessary to make Cox-2. These instructions are carried in small molecule called messenger RNA. When the blood platelet signals the monocyte, the cell decodes the instructions from the Cox-2 gene in a process called transcription. This results in production of messenger RNA that specifically codes for Cox-2. After the messenger RNA is transcribed, the blood platelet then sends a second signal to the monocyte that regulates stability of the Cox-2 messenger RNA and further decoding of the genetic information. This process, called translation, results in production of the Cox-2 protein and controls how much, and at what time point, it is produced.
Drugs called non-steroidal anti-inflammatory agents, which inhibit production of Cox-2 and reduce inflammation, are some of the most widely used medications in the world for arthritis and other inflammatory diseases. But some of these drugs, also called Cox-2 inhibitors, such as Vioxx, increase the chance of heart attack.
Identifying the signaling mechanism between blood platelets and monocytes makes it possible to develop new drugs to modify Cox-2 production. "Knowing these steps gives you an initial blueprint about how to modify Cox-2," Zimmerman said. Understanding this mechanism may enable researchers to develop drugs that help people during a heart attack, or prevent heart attack, stroke or other inflammatory diseases.
The study's other co-authors from the 亚洲自慰视频 of Utah include Andrew S. Weyrich, Ph.D., research associate professor of internal medicine; Mark L. Martinez, M.D., visiting instructor of internal medicine; and Neal D. Tolley of the Program in Human Molecular Biology and Genetics.
Steven M. Prescott, M.D., formerly with the 亚洲自慰视频 of Utah medical school and the 亚洲自慰视频's Huntsman Cancer Institute, also co-authored the study. Zimmerman and Prescott were part of an earlier collaboration at the 亚洲自慰视频 that was one of the first to clone the Cox-2 gene.
Zimmerman noted clinical trials of drugs that target the cross talk between platelets and monocytes, and the Cox-2 pathway, are in the planning stages.