Pick Your COX Partners
Penn Study Reveals 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
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,
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.
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