Pick your COX partners

COX enzymes work together in ways that suggest new biological roles, drug targets

(Philadelphia, PA) Researchers at the University of Pennsylvania School of Medicine and Queen's University, Ontario, Canada report in the online edition of Nature Medicine this week that the COX enzymes well-known for their contrasting role in cardiovascular biology interact physically to form a previously unrecognized biochemical partnership and function in the development of blood vessels in a mouse model. Collaborators Garret FitzGerald, MD, Director of Penn's Institute for Translational Medicine and Therapeutics, and Colin Funk from Queen's University, say that the findings suggest new biological, developmental, and therapeutic roles for COX enzymes and prompt a re-evaluation of basic assumptions about the role of COX enzymes in disease.

COX-2 is the target of the now familiar COX inhibitors Vioxx and Celebrex. COX-1, the less celebrated sister, is the target of low-dose aspirin and older drugs, such as Advil and Naprosyn, which inhibit both COX-1 and COX-2 to prevent heart disease.

Researchers have known for some time that COX-1 and COX-2 pair up to function in the body. Even though they are interlocked, only one of them is active at a time in processing their substrate, arachidonic acid from which prostaglandins, the fatty mediators of pain, inflammation, and heart attacks are formed. The molecular structures of COX-1 and COX-2 are remarkably similar, but a subtle variation in their structure permits the construction of drugs that are selective in their inhibition for COX -2.

For this study the researchers developed a novel genetic mouse model that mimics the physiology of COX-2 inhibition. The investigators demonstrated that the COX-1:COX-2 partnership, or heterodimer, appears to play a critical role in the transformation that occurs in the blood vessels of newly born mice, shortly after birth, namely the closing of the ductus arterious. This necessary developmental step permits newborns to function independently from their mother.

"These observations prompt us to explore new roles for the COX enzymes in biology," says FitzGerald. "Perhaps their embrace will extend to other enzymes, such as the lipoxygenases and the nitric oxide synthases, in ways that prompt us to re-evaluate basic assumptions about the role of COX enzymes in physiology and disease."

"Perhaps this combination of COX enzymes will represent a new drug target," speculates Funk. "Blocking the COX dimer may alter the pattern of usefulness and/or safety that we associate with existing non-steroidal anti-inflammatory drugs." Funk, who has collaborated with FitzGerald at Penn over the last decade on this line of research, is now the Canada Research Chair of Physiology at Queen's University, Ontario.

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Co-authors are by Ying Yu, Jinjin Fan, Xin-Sheng Chen and Dairong Wong, all postdoctoral fellows at Penn's Institute for Translational Medicine and Therapeutics; Andres Klein-Szanto, Fox Chase Cancer Center, Philadelphia; and Robert Campbell, from Queens University.

This work was supported by grants from the National Institutes of Health and the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Ontario.

This release and related images can be found at http://www.uphs.upenn.edu/news/

PENN Medicine is a $2.9 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.

Penn's School of Medicine is ranked #2 in the nation for receipt of NIH research funds; and ranked #3 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.

The University of Pennsylvania Health System includes three hospitals [Hospital of the University of Pennsylvania, which is consistently ranked one of the nation's few "Honor Roll" hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; and Penn Presbyterian Medical Center]; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home care and hospice.


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