Controlling Smooth Muscle Growth: Combining NO and the Fas ligand with stent treatment

Since heart disease is the leading cause of death in America, treatments like using drug-eluting stents to combat atherosclerosis—the narrowing of blood vessels due to plaque buildup—have become essential. However, bare metal stents, tubes inserted into blood vessels to help keep them open, come with the unfortunate drawback of triggering excess growth of smooth muscle. Also known as smooth muscle proliferation, this excess growth of smooth muscle narrows the blood vessel, negating the effect of the stent.

Current solutions use drug-eluting stents, which release drugs that prevent smooth muscle proliferation. However, the drugs used are non-selective. In other words, while they prevent excess growth of smooth muscle cells, they also prevent the proliferation of endothelial cells, the cells lining the inside of blood vessels, causing platelets to adhere to the insides of blood vessels, resulting in blood clots. Blood clots mandate additional antiplatelet therapy to prevent clotting, putting the patient at higher risk of bleeding out upon injury. “Thus, while trying to solve a problem, another major problem is caused by these currently available drug-eluting stents,” said Mehmet Kural, a researcher at the Yale School of Medicine.

In response to this problem, a team of Yale researchers led by Kural investigated the use of nitric oxide (NO) paired with the Fas ligand, which binds to Fas receptors on smooth muscle cells to trigger apoptosis, or cell death. This binding prevents smooth muscle proliferation while endothelial cells, which are far more resistant to this type of Fas-regulated cell death, are able to proliferate. NO has been found to increase the number of Fas receptors on smooth muscle cells, so when used in conjunction with the Fas ligand, this method effectively prevents smooth muscle proliferation and dramatically reduces the likelihood of stent failure.

So far, this treatment has been tested on pig coronary arteries and has been shown to be effective. “I anticipate human trials…in five years, but before that we need to do large animal experiments and toxicity studies,” Kural said.