(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.
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
“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.
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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