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New Type Of Pain Reliever May Benefit The Heart

Date:
September 13, 2006
Source:
University of Pennsylvania School of Medicine
Summary:
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 that steer clear of heart-disease risk and work to reduce it.

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.

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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 it.

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.


Story Source:

The above story is based on materials provided by University of Pennsylvania School of Medicine. Note: Materials may be edited for content and length.


Cite This Page:

University of Pennsylvania School of Medicine. "New Type Of Pain Reliever May Benefit The Heart." ScienceDaily. ScienceDaily, 13 September 2006. <www.sciencedaily.com/releases/2006/09/060912230236.htm>.
University of Pennsylvania School of Medicine. (2006, September 13). New Type Of Pain Reliever May Benefit The Heart. ScienceDaily. Retrieved November 26, 2014 from www.sciencedaily.com/releases/2006/09/060912230236.htm
University of Pennsylvania School of Medicine. "New Type Of Pain Reliever May Benefit The Heart." ScienceDaily. www.sciencedaily.com/releases/2006/09/060912230236.htm (accessed November 26, 2014).

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