Study clarifies action of potential new class of pain relievers that may benefit, not hurt, the heart

The shows the effects of myeloid cell mPGES-1 deletion on plaque macrophage abundance, less in the myeloid mPGES-1 knockout versus wild type. Credit: Lihong Chen, MD, PhD, Perelman School of Medicine, University of Pennsylvania.

Nonsteroidal antinflamatory drugs (NSAIDs) that block an enzyme called COX-2 relieve pain and inflammation but can cause heart attacks, stroke, heart failure, and even sudden cardiac death. This has prompted a decade-plus search for safer, but still effective, alternatives to these commonly prescribed, pain-relieving drugs.

Building on previous work that showed that deleting an enzyme in the COX-2 pathway in a mouse model of heart disease slowed the development of atherosclerosis, a team from the Perelman School of Medicine at the University of Pennsylvania has now extended this observation by clarifying that the consequence of deleting the enzyme mPEGS-1 differs, depending on the cell type in which it is taken away.

In a report published this week in the online edition of the Proceedings of the National Academy of Sciences, Lihong Chen, MD, PhD, a postdoctoral fellow in the lab of senior author Garret FitzGerald, MD, FRS, director of the Institute for Translational Medicine and Therapeutics, found that deleting mPGES-1 in macrophages markedly slows the rate at which arteries harden in mice with high levels of cholesterol. This results from a reduction in the oxidative damage done to the vessel wall due to a shift in the genes expressed because of the suppression of PGE2, a cardioprotective fat. By contrast, deletion of mPGES-1 in vascular cells had no effect.

Chen and FitzGerald are currently working on ways to deliver inhibitors of mPGES-1 selectively to the macrophages, immune system cells that live primarily in connective tissue and blood and ingest foreign particles and infectious microbes.

"While deletion or inhibition of COX-2 in mice elevates their blood pressure and predisposes them to clotting and hardening of the arteries due to suppressing the cardioprotective lipid prostacyclin, deleting mPGES-1 avoids these effects and even restrains the development of atherosclerosis," explains FitzGerald.

"Taken together these studies add more evidence that targeting the enzyme mPEGS-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," says Chen.

In earlier studies, Chen showed a similarly beneficial effect of targeting macrophages in limiting the response to vascular injury of unwanted cell proliferation, such as might complicate angioplasty in humans. "Both sets of studies afford a rationale for targeted inhibition of macrophage mPGES-1 for cardiovascular benefit" says FitzGerald.

Indeed, in other ongoing studies in the FitzGerald lab, Chen has shown that macrophage mPGES-1 plays a dominant role in mediating the pain caused by PGE2. "What is exciting here," says Chen, "is the prospect of retaining the benefit of NSAIDs while substituting cardiovascular benefit for risk."

NSAIDs like ibuprofen (Advil) and naproxen (Naprosyn) relieve pain and inflammation by blocking COX enzymes that help make prostaglandins. COX-2 is the most important source of the two prostaglandins - PGE2 and prostacyclin - that mediate pain and inflammation. However, COX-2-derived prostacyclin particularly may also protect the heart, and loss of this function 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 yet are safe for the cardiovascular system. This is where mPGES-1 comes in – it converts PGH2 (a chemical product of COX-2) into PGE2. In a 2006 study, the FitzGerald lab found that mPGES-1 deletion did not elevate or predispose mice to thrombosis, probably by avoiding suppression of prostacyclin. In the absence of the enzyme, the diseased vessels were depleted of macrophages, which led to the predominance of vascular smooth muscle cells in blood vessel walls.

More information: Myeloid cell microsomal prostaglandin E synthase-1 fosters atherogenesis in mice, PNAS, 2014. www.pnas.org/cgi/doi/10.1073/pnas.1401797111

add to favorites email to friend print save as pdf

Related Stories

NSAIDs and cardiovascular risk explained

May 02, 2012

After nearly 13 years of study and intense debate, a pair of new papers from the Perelman School of Medicine, at the University of Pennsylvania have confirmed exactly how a once-popular class of anti-inflammatory drugs leads ...

Researchers find that influenza has an Achilles' heel

Apr 10, 2014

Flu epidemics cause up to half a million deaths worldwide each year, and emerging strains continually threaten to spread to humans and cause even deadlier pandemics. A study published by Cell Press on April 10 in the journal ...

New study cautions use of drugs to block 'niacin flush'

Apr 09, 2012

Niacin, or vitamin B3, is the one approved drug that elevates "good" cholesterol (high density lipoprotein, HDL) while depressing "bad" cholesterol (low density lipoprotein , LDL), and has thereby attracted much attention ...

Team discovers potential new way to treat anxiety

Aug 04, 2013

Chemically modified inhibitors of the COX-2 enzyme relieve anxiety behaviors in mice by activating natural "endocannabinoids" without gastrointestinal side effects, Vanderbilt University scientists will report ...

Recommended for you

Mirabegron for overactive bladder: Added benefit not proven

12 minutes ago

Mirabegron (trade name: Betmiga) has been approved since December 2012 for the treatment of adults with overactive bladder. In an early benefit assessment pursuant to the Act on the Reform of the Market for Medicinal Products ...

Novartis Japan admits concealing drug side effects

Sep 01, 2014

The Japanese unit of Swiss pharma giant Novartis has admitted it did not report more than 2,500 cases of serious side effects in patients using its leukaemia and other cancer drugs, reportedly including some fatalities.

Most US babies get their vaccines, CDC says

Aug 28, 2014

(HealthDay)—The vast majority of American babies are getting the vaccines they need to protect them from serious illnesses, federal health officials said Thursday.

User comments