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.