The Johns Hopkins researchers who first showed that the commonly used blood pressure drug losartan may help prevent life-threatening aneurysms of the aorta in patients with Marfan syndrome have now discovered new clues about the precise mechanism behind the drug’s protective effects.
The team’s findings not only answer many lingering questions — including how exactly the drug works and whether other classes of blood-pressure medication may work as well as or better than losartan — but also identify new targets for treating Marfan and other connective-tissue disorders.
In two separate papers published in the April 15 issue of Science, the researchers show that losartan neutralizes a rogue protein and in doing so halts the dangerous ballooning of the heart’s main blood vessel, the aorta.
“Our research has decoded the exact cascade of events triggered by the genetic glitch in Marfan that culminates in weakening of the aorta, its gradual enlargement and tearing,” says senior investigator Harry “Hal” Dietz, M.D., a cardiologist at Johns Hopkins Children’s Center, professor in the McKusick-Nathans Institute of Genetic Medicine at Hopkins and director of the William S. Smilow Center for Marfan Research.
“Understanding the cellular cascade leading up to Marfan’s most serious complication will allow us to design therapies that precision-target each step in this harmful sequence of events,” Dietz adds.
Dietz’s research has previously shown that the dangerous stretching of the aorta in those born with the genetic disorder stems from the excessive activity of a protein called TGF-beta, believed to cause damage by setting off aberrant signals inside cells that make up blood vessels. The new research, conducted in mice that were genetically engineered to develop Marfan, identifies one of these signals as a critical communication channel that sets off a dangerous cross-talk between TGF-beta and a protein called ERK. TGF-beta activates ERK, which causes the aorta to stretch and grow aneurysms, the researchers found.
The research further shows that two other proteins, AT1 and AT2, play opposing roles in the cross-talk between TGF-beta and ERK, and that turning one off while keeping the other intact is critical in preventing aneurysms. Researchers have long suspected that AT1 can cause damage to the aorta by activating TGF-beta, but AT2’s role has remained unclear — until now.
To explain the role of AT2 in aneurysm formation, the researchers treated mice with Marfan with either losartan, a known inhibitor of AT1, or enalapril, a drug that shuts off both AT1 and AT2. The aortas of mice treated with losartan stopped growing in the area where aneurysms tend to form. Mice treated with enalapril, however, showed barely any improvement. The discovery led researchers to conclude that blocking the AT1 alone can slow growth and avert aneurysm formation, but blocking both AT1 and AT2 would not. In other words, keeping AT2 intact halted the dangerous interplay between TGF-beta and ERK. Losartan blocked AT1 but spared AT2, thus turning off ERK. Enalapril shut off both and had no effect on ERK.
Because TGF-beta is already a suspect in other connective-tissue diseases, these new revelations about its modus operandi may pave the way to new therapies for such disorders, the investigators say.
“Precision-targeting AT1 to shut it off, while leaving AT2 intact is the way to go,” says lead author Jennifer Pardo Habashi, M.D., a cardiologist at Hopkins Children’s. “Now that we know what makes losartan so effective, we can start looking for other medications that may be even better at preventing aortic damage.”
The investigative team also tested a candidate compound that selectively blocks ERK and showed that it completely halted aneurysm growth in mice with Marfan. Yet another compound that blocks another one of TGF-beta’s communication channels, called JNK, was nearly as effective in curbing aneurysm growth.
Dietz identified the Marfan gene in the 1990s and led the scientific team that in 2006 first described losartan’s effect on the aorta.
A small Hopkins study in children has already shown that losartan can slow enlargement of the aorta over time. Based on these findings, larger clinical trials are already under way at Hopkins Children’s and other institutions.
Other Hopkins researchers involved in the two studies were Tammy Holm, Jefferson Doyle, Djahida Bedja, YiChun Chen, Christel van Erp, Hamza Aziz, Mark Lindsay, David Kim, Daniel Judge, Alexandra Modiri, Florian Schoenhoff and Ronald Cohn.
Co-investigators from other institutions included Bart Loeys of Ghent University in Belgium, and Craig Thomas, Samarjit Patnaik, and Juan Marugan, of the National Institutes of Health.
The research was funded by the National Institutes of Health, the Howard Hughes Medical Institute, the Smilow Center for Marfan Research at Hopkins and The National Marfan Foundation.