A Massachusetts General Hospital research team has identified a nucleoprotein complex that is responsible for breaking down the arterial wall in aortic aneurysm.
With the help of insights gleaned from patients with a genetic predisposition to aortic aneurysm, a research team led by Massachusetts General Hospital's Mark Lindsay, MD, PhD, has identified a nucleoprotein complex that initiates a series of events leading to dysfunction of smooth muscle cells in the aortic wall.
Dr. Lindsay is a cardiologist and an investigator in the Cardiovascular Research Center at Mass General. The lead author on the study was Christian L. Lino Cardenas, PharmD, MSc, PhD.
This new research was published in Nature Communications on March 8. A companion study exploring a potential treatment target was published on the same day in JCI-Insight.
The protein complex consisting of the proteins HDAC9 and BRG1 as well as an RNA called MALAT1, could lead to new treatments for individuals with both hereditary aortic aneurysm and the more common sporadic forms of aortic aneurysm. In addition, these findings may have implications beyond the treatment of aortic aneurysm as the HDAC9 gene has been linked to other heart and vascular disorders such as heart attacks, strokes, intracranial aneurysm, and hypertension.
Aneurysms, Dissections and Ruptures
An aortic aneurysm occurs when the wall of the aorta is weak, typically developing a telltale bulge due to internal pressure. An aneurysm is not harmful in and of itself, but it indicates a weakening of the wall that can lead to a condition called aortic dissection.
An aortic dissection occurs when the medial (inner) layer of the aorta tears, allowing blood to flow between the layers of the aorta. This condition can cause sudden, severe chest or back pain, prevent blood from reaching other organs and can be as fatal as a severe heart attack. If the artery ruptures completely, it can result in massive internal bleeding. An aortic rupture is fatal in 90 percent of cases.
Finding Clues in Genetics
Dr. Lindsay explains that there is a small percentage of patients who have a genetic predisposition to aortic aneurysm, a condition known as hereditary thoracic aortic aneurysm and dissection (HTAD).
There are two major families of gene mutations underpinning HTAD. Although each mutation is located in a different gene family, they produce a similar disease pathology.
By comparing and contrasting effects from perturbing the two gene families, Dr. Lindsay's team identified a protein called HDAC9 that was upregulated (expressed more than normal) in tissue samples.
"This protein caught our eye because it has been identified in other human genetic studies in diseases such as stroke, heart attack and vascular complications," he explains. "It was known to be important, but it wasn’t clear how it worked and what it was doing to facilitate these diseases."
Upon further investigation, the team learned that HDAC9 forms a complex with another protein called BRG1 and a long non-coding RNA called MALAT1. This complex then recruits a second, larger complex called PRC2. The PRC2 complex then turns off the genes associated with contraction in smooth muscle cells.
“The aorta is comprised almost exclusively of smooth muscle cells in the wall,” Lindsay explains. "This HDAC9 complex is part of the machinery that turns these cells from their normal state into a more problematic state that breaks down the structural integrity of the aortic wall."
To confirm the role of the HDAC9 complex, the team cross-bred mice that were genetically engineered to remove either HDAC9 or MALAT1 with mouse models of Marfan syndrome, a form of HTAD. These mice developed aneurysm more slowly than control subjects.
More research is now needed to confirm the role of HDAC9 in other heart disorders, including non-genetic forms of aortic aneurysm, as well as heart attacks and strokes.
"We don't know for sure, but we think that this discovery may have broader applicability than just in patients with genetic mutations, because in human samples of non-genetic aortic dissection, we were able to see the same upregulation of HDAC9," Dr. Lindsay says.
"We also want to investigate the role of this complex in other common human diseases such as strokes and heart attacks that are driven by atherosclerosis, and hypertension (high blood pressure), which can be driven by vascular stiffness and have serious complications."
Therapeutic Tests and Next Steps
In a second companion study detailed in JCI-Insight, Dr. Lindsay and his team tested a known PRC2 inhibiting drug on mouse models of Marfan syndrome and found that it slowed the progression of aortic aneurysm.
While the results are encouraging, Dr. Lindsay cautions that drugs the team used were chemotherapy drugs with high levels of systemic toxicity, which would not be suitable for patients in need of long term management of an aortic aneurysm.
“Basically, we would need new, more targeted therapeutics of the same class, or probably just a different therapeutic with less toxicity.”
This work was supported by the Fredman Fellowship, the Toomey Fund for Aortic Dissection Research, and the Hassenfeld Fellowship in addition to a grant from the NHLBI (HL130113).