Researchers have found that inhibiting one step of prostaglandin synthesis specifically in macrophages appears to have cardiovascular benefits, an ironic new twist on the relationship between nonsteroidal anti-inflammatory drugs (NSAIDs) and the cardiovascular system.

The findings could point the way to new cardiovascular drugs as well as better NSAID painkillers.

Older NSAIDs such as ibuprofen are stalwarts in the painkiller world. They work by preventing the cyclooxygenase (COX) enzyme from producing prostaglandins, whose major physiological role is to induce "pain, inflammation and fever," Lihong Chen told BioWorld Today.

Chen is at the University of Pennsylvania and the lead author of a paper describing the new findings, which she and her colleague reported in the April 21, 2014, online edition of the Proceedings of the National Academy of Sciences.

If the basic role of prostaglandins is simple, the details of their production are anything but. There are two types of cyclooxygenases, and one of the biggest pharmacological misfires of the last decade was the development of painkillers that were specific to one of them, the COX-2 inhibitors.

Those drugs, however – Vioxx (rofecoxib, Merck & Co. Inc.), Celebrex (celecoxib, Pfizer Inc.) and Bextra (valdecoxib, Pfizer Inc.) – were found to raise the risk of heart attack and stroke in the patients taking them.

Vioxx and Bextra were taken off the market in 2004, and Celebrex, while still available, carries a black-box warning about its cardiovascular risks. Merck, which was slow to admit that Vioxx caused any cardiovascular problems, has paid billions of dollars to settle thousands of consumer lawsuits claiming the company knew of those risks early on.

Whatever their cardiovascular risks, however, the COX-2 inhibitors were undeniably effective painkillers. And so "a lot of researchers have been looking for alternative ways" to tinker with prostaglandin production in a way that does not lead to cardiovascular side effects, Chen said.

Those side effects are due to the fact that inhibiting COX-2 shuts down not just the production of prostaglandin E2, which is responsible for its analgesic effects. Because COX-2 works fairly early in the synthesis of prostaglandin, it also inhibits the production of another protein, prostacyclin, which is heart-protective.

One alternative approach has focused on inhibiting the enzyme prostaglandin E synthase-1, which is the last enzyme in the production chain that leads to prostaglandin E2. In previous work, the Penn team had shown that blocking prostaglandin E synthase-1 did not appear to lead to the kind of cardiovascular risks that COX-2 inhibition did.

In those studies, there were also hints that the effects of shutting down the enzyme varied by cell type. In the work now published in PNAS, the team followed up on those hints, looking at the effects of knocking out prostaglandin E synthase-1 in several different cell types.

They found that in both male and female mice fed a high-fat diet, knocking out prostaglandin E synthase-1 specifically in macrophages could protect the animals from heart disease. Animals lacking the enzyme in endothelial or vascular smooth muscle cells, on the other hand, developed plaques – which develop when macrophages mount an immune response to LDL cholesterol deposits in artery walls – at the same rate as control animals.

Altogether, Chen said, the work suggested that targeting prostaglandin E synthase-1 "could result in a new class of nonsteroidal anti-inflammatory drugs that steer clear of heart-disease risk and even work to reduce it. . . . What is exciting here is the prospect of retaining the benefit of NSAIDs while substituting cardiovascular benefit for risk." She and her colleagues want to test whether inhibiting prostaglandin production in macrophages can reverse established atherosclerosis as well as prevent it from starting in the first place.

If that is the case, there might in time be NSAIDs that are not just safer painkillers, but, if they are targeted specifically to macrophages, could fight atherosclerosis instead of causing it. And as cell-specific delivery goes, targeting macrophages is relatively easy – their whole mission in life is to take up cellular debris, and packaging a drug in liposomes or nanoparticles can be used for specific delivery of drugs.