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Pick your COX partners

June 08, 2006

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.

University of Pennsylvania School of Medicine