Penn Study Suggests a New Type
of Pain Reliever That May Benefit the Heart
(Philadelphia, PA) - Building on previous work, researchers at the University
of Pennsylvania School of Medicine have found that deleting an
inflammation enzyme in a mouse model of heart disease slowed the development
of atherosclerosis. What's more, the composition of the animals’
blood vessels showed that the disease process had not only slowed, but
also stabilized. This study points to the possibility of a new class of
nonsteroidal anti-inflammatory drugs (NSAIDs) that steer clear of heart-disease
risk and work to reduce it.
Senior author Garret FitzGerald, MD, Director of the
Institute for Translational Medicine and Therapeutics at Penn, and colleagues
report their findings this week in the online edition of the Proceedings
of the National Academy of Sciences.
NSAIDs like ibuprofen (Advil) and naproxen (Naprosyn) relieve pain and
inflammation by blocking the cyclooxygenases, or COX enzymes (COX-1 and
COX-2). These enzymes help make fats called prostaglandins. COX-2 is the
most important source of the two prostaglandins - PGE2 and prostacyclin
- that mediate pain and inflammation. However, COX-2-derived PGE2 and
prostacyclin may also protect the heart, and loss of this function - particularly
suppression of prostacyclin - explains the risk of heart attacks from
NSAIDs that inhibit COX-2, such as rofecoxib (Vioxx), valdecoxib (Bextra),
and celecoxib (Celebrex).
The problems with COX-2 inhibitors have prompted the search for alternative
drug targets that suppress pain and inflammation yet are safe for the
cardiovascular system. One possibility is an enzyme called mPGES-1, which
converts PGH2 (a chemical product of COX-2) into PGE2. Previous studies
at other institutions in mice lacking mPGES-1 suggest that inhibitors
of this enzyme might retain much of the effectiveness of NSAIDs in combating
pain and inflammation. However, unlike COX-2 inhibition or deletion, the
Penn researchers had found that mPGES-1 deletion did not elevate blood
pressure or predispose the mice to thrombosis. This work began to raise
the possibility that mPGES-1 inhibitors might even benefit the heart.
In the PNAS study, the researchers studied the impact of deleting
the mPGES-1 gene in mice predisposed to hardening of the arteries. Removing
the enzyme had a dramatic effect on the development of the disease. "Both
male and female mice slowed their development of atherosclerosis,"
explains first author Miao Wang, PhD, a postdoctoral
fellow in the Penn Institute.
The composition of the blood vessels of the transgenic mice suggested
that the disease process had not only slowed, but also stabilized. Collaborators
Ellen Pure and Alicia Zukas at the Wistar Institute examined the detailed
structure of the diseased arteries. Deleting mPGES-1 resulted in a dramatic
change in the cellular constituents of the atherosclerotic plaques seen
in the transgenic mice. In the absence of the enzyme, the diseased vessels
were depleted of immune cells called macrophages, which led to the predominance
of vascular smooth muscle cells in blood vessel walls. In turn, this led
to a switch in the form of collagen - a fibrous structure that contributes
to the fabric of plaques - to a more stable and benign form.
"It seems that it is the complete reverse of the mechanism that creates
problems for COX-2 inhibitors," says FitzGerald. Mice lacking mPGES-1
boost their production of prostacyclin, the major heart-protecting fat
produced by COX-2. They do this by redirecting prostacylcin to vascular
smooth muscle cells. The same mechanism explains the group's earlier findings
on blood pressure and thrombosis.
"It remains to be determined whether specific inhibitors of mPGES-1
can replicate the consequences of removing the gene" explains FitzGerald,
"And if so, whether these results will translate from mice to humans."
In the meantime, these results, say the investigators, will fuel interest
in the possibility of a new class of "super NSAIDs," which may
not just avoid the risk of heart disease, but also actually work to diminish
Study co-authors are Yiqun Hui and Emanuela Riciotti, both from Penn,
as well as Alicia Zukas and Ellen Pure from the Wistar Institute, Philadelphia.
This research was funded by the National Heart, Lung, and Blood Institute.
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