Aortic aneurysms — dangerous bulges in the body’s main artery, the aorta — are becoming increasingly common as more people live longer. Aneurysms are typically silent and cause no symptoms. Undetected, they can lead to fatal ruptures of the aorta.
Now a study led by Harvard Medical School researchers at Mass General Brigham and funded in part by the National Institutes of Health has uncovered a new pathway that fuels the rise of aortic aneurysms. The research offers clues for treatment and prevention of these aneurysms that could also address another common condition: hypertension, which affects nearly half of all US adults.
Scientists have long suspected that oxidative stress — chemical damage that occurs in cells from the buildup of toxic molecules called free radicals — plays a role in both disorders. Yet whether and how oxidative stress causes either disease has remained unclear.
The new study, based on experiments in mice, sheds light on the molecular origins of aneurysms and pinpoints a culprit behind a signaling cascade that fuels high blood pressure and aneurysms.
The findings, described May 1 in The Journal of Clinical Investigation, could inform the design of new treatments for these dangerous and often-silent killers.
“Our research has identified an entirely new drug target for the prevention and treatment of aortic aneurysms and hypertension,” said senior author Thomas Michel, HMS professor of medicine and senior cardiovascular physician at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system.
While much work remains before the findings can be translated to humans, the study offers a critical clue into a longstanding puzzle. Currently, there are no treatments to prevent aneurysms from forming in the first place, or to halt their growth once they develop.
“If replicated in further animal studies and in humans, these insights could pave the way to new drugs aimed at halting aneurysms before they arise, grow, and become life-threatening,” Michel said.
The team, led by Apabrita Ayan Das, a research fellow in the Michel lab, induced controlled oxidative stress in the lining of mouse blood vessels . Over time, the animals developed both hypertension and aortic aneurysms. Strikingly, the mice grew aneurysms in the abdominal portion of the aorta, but not in the portion located in the chest. This finding points to key biological differences that cause these distinct regions of the aorta to respond differently to stress or injury.
Further analysis revealed a culprit: an enzyme called DUSP3. Under oxidative stress, the enzyme altered cell signaling and caused cells in the lining of blood vessels to behave abnormally. In response to this process, animals developed persistently elevated blood pressure and aneurysmal bulges on the walls of the aorta. When the researchers gave mice a chemical that blocked DUSP3, the animals didn’t show signs of hypertension or aneurysms, even in the presence of blood-vessel damaging oxidative stress.
The findings suggest that the DUSP3-blocking compound could become the basis for new drugs to treat or even prevent aneurysms in the abdominal aorta. Such drugs, the researchers noted, could also protect against hypertension.
The study is the first to implicate DUSP-3 in aneurysm formation. The researchers are now investigating whether DUSP3 might also play a role in other diseases linked to oxidative stress, such as Alzheimer’s and atherosclerosis.
Adapted from a Mass General Brigham news release.
Authorship, funding, disclosures
Additional authors include Markus Waldeck-Weiermair, Shambhu Yadav, Fotios Spyropoulos, Arvind Pandey, Tanoy Dutta, and Taylor A. Covington.
This study was supported by the NIH (R33 HL157918; R21 AG063073; R01 HL152173; K08 HL168240) and an Austrian Science Fund 21 Fellowship (J4466-B).
A preliminary patent application (number 63/771,959) for the use of DUSP-3 inhibitors in treatment of disease states caused by oxidative stress has been prepared.
