Oxidative stress can occur when our cells are exposed to harmful molecules called "reactive oxygen species" over time. These reactive oxygen species can damage cells and are found in important disease states, such as high blood pressure and aortic aneurysms. Aortic aneurysms are balloon-like swellings of the body's largest artery and are often fatal when the aneurysm bursts.
Investigators at Mass General Brigham have discovered a new pathway that may lead to a treatment for high blood pressure and aortic aneurysms. By creating a new laboratory model for studying these conditions, the team treated hypertension and aortic aneurysms by targeting a protein that they discovered to be involved in the vascular cells' response to oxidative stress. The findings are published on May 1, 2025 in The Journal of Clinical Investigation .
"Each year, approximately 15,000 Americans die from aortic aneurysms, yet the causes of aortic aneurysms are incompletely understood. And hypertension—high blood pressure—affects half of all adults in this country, and there is a large unmet need for the development of new antihypertensive drugs," said senior author Thomas Michel, MD, PhD, who is a senior physician in Cardiovascular Medicine at Brigham and Women's Hospital, a founding member of the Mass General Brigham healthcare system. Michel is also a professor at Harvard Medical School. "Our studies have identified a potentially important and entirely new drug target for the prevention and treatment of hypertension and aortic aneurysms."
Although oxidative stress has long been associated with hypertension and aortic aneurysms, it was unclear whether it actually causes these complex medical conditions. To investigate, Michel and his colleagues created a transgenic mouse model in which oxidative stress can be dynamically modulated within blood vessels using a new scientific strategy termed "chemogenetics."
The studies, led by Apabrita Ayan Das, PhD, a postdoctoral research fellow in the Michel laboratory, found that oxidative stress affected proteins in the blood vessel walls, causing vascular cells to change and become more prone to aneurysms and hypertension. The research team found that one of the key players in this process is a protein called DUSP-3. When the scientists gave mice with oxidative stress an inhibitor of DUSP-3, the treatment blocked the development of aortic aneurysms and reduced hypertension.
"DUSP-3 had never previously been implicated in hypertension or aneurysm formation. It could be an important drug target to treat or prevent these conditions," said Michel. "We are also expanding our studies of DUSP-3 inhibition to study other vascular disease states associated with oxidative stress, including Alzheimer's disease, atherosclerosis, and aging."
Authorship: In addition to Michel and Das, Mass General Brigham authors include Markus Waldeck-Weiermair, Shambhu Yadav, Fotios Spyropoulos, Arvind Pandey, Tanoy Dutta, and Taylor A. Covington.
Disclosures: 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.
Funding: This study was supported by National Institutes of Health (NIH) (grants R33 HL157918, R21 AG063073, R01 HL152173, and K08 HL168240) and a FWF 21 Fellowship J4466-B.
Paper cited: Das, AA et al. "Differential aortic aneurysm formation provoked by chemogenetic oxidative stress" JCI DOI: 10.1172/JCI188743
Read the paper: https://www.jci.org/articles/view/188743/ga
