Progeria’s Cardiovascular Complications Could Be Treated with New Protein Finding

The results of a University of Maryland (UMD)-led study could point to new and improved treatment approaches for Hutchinson-Gilford progeria syndrome (HGPS), a rare genetic disorder that causes accelerated aging in children, and for which there is no known cure.

Researchers in the lab of UMD Cell Biology and Molecular Genetics Professor Kan Cao, PhD, collaborating with scientists at the National Institutes of Health (NIH) and Duke University, identified a protein, angiopoietin-2 (Ang2), that was linked to the cardiovascular health of animal models with progeria, and which could have relevance for human therapy. Heart failure and stroke are the most common causes of death for people with HGPS, who typically have a life expectancy of between 6 and 20 years.

The new findings are “highly promising,” suggested biological sciences PhD student Sahar Vakili. “This could pave the way for new treatments targeting cardiovascular complications in HGPS, which are currently a major cause of mortality in the affected children. Beyond progeria, insights gained from this research might also be applicable to other age-related diseases where endothelial dysfunction plays a role.”

Vakili is first author of the researchers’ published paper in Aging Cell, titled “Angiopoietin-2 reverse endothelial cell dysfunction in progeria vasculature,” in which they concluded, “Our investigation demonstrates a novel function for Ang2 or its agonists as a potential therapeutic for HGPS.”

HGPS is a rare premature aging disorder in children caused by a point mutation in the lamin A gene, LMNA, which in its normal form produces the protein, lamin, but when mutated in HGPS results in a toxic form of lamin A called progerin.

Sometimes described as the “Benjamin Button disease,” HGPS causes a variety of symptoms associated with aging, including skin wrinkling, joint stiffness, and the loss of hair and body fat. “Accelerated atherosclerosis leading to heart attack and stroke are the major causes of death in these patients,” the authors noted. “Endothelial cell (EC) dysfunction contributes to the pathogenesis of HGPS related cardiovascular diseases (CVD).”

Endothelial cells line the body’s vascular system—including the heart—and control substances moving in and out of the bloodstream. Endothelial cell malfunction can lead to an array of conditions, including cardiovascular disease, stroke, blood clots and atherosclerosis (buildup of plaque inside the arteries). “Endothelial cell–cell communications are important in the development of the vasculature, and their disruptions contribute to cardiovascular pathology,” the team continued. “However, it is unclear how progerin interferes with such communications that lead to vascular dysfunction.”

To better understand how progeria causes cardiovascular complications, Cao, Vakili, and colleagues wanted to investigate the signals sent by endothelial cells that ultimately lead to HGPS-related cardiovascular disease. “We hypothesized that progerin expression in ECs interferes with their proper communication, leading to vascular dysfunction,” they noted.

The results of their collective investigations, including studies in a mouse model of HGPS, discovered that angiopoietin-2, a protein that regulates the formation of new blood vessels and the flow of substances through blood vessel walls, is significantly impaired in individuals with progeria, affecting the overall function of their endothelial cells.

 

The work identified Ang2 as a downregulated signaling molecule in HGPS,  and showed that Ang2 mRNA and protein were downregulated in the aortas of the HGPS mouse model. The researchers also discovered that they could use Ang2 to “rescue” endothelial cells, improving their health despite dysfunction stemming from HGPS. Ang2 enhanced the formation of blood vessels, normalized cell migration and restored nitric oxide levels, which are crucial for a healthy vascular system, by activating endothelial nitric oxide synthase (eNOS). “Ang2 treatment also improves endothelial cell signaling to vascular smooth muscle cells, suggesting it could be a potential therapy for vascular dysfunctions in HGPS,” Vakili said.

“Addition of Ang2 to HGPS ECs rescues vasculogenesis, normalizes endothelial cell migration and gene expression, and restores nitric oxide bioavailability through eNOS activation,” the team wrote. “Furthermore, Ang2 addition reverses unfavorable paracrine effects of HGPS ECs on vascular smooth muscle cells.” To conclude, they stated, “… the remarkable improvements in HGPS ECs after a single treatment with Ang2 collectively suggest that this growth factor may have therapeutic potential to treat vascular disease in HGPS.”

Current treatments for HGPS can help reduce the risk of fatal complications like heart attack and stroke, but they do not target the underlying disease. Cao explained that their research is unlikely to offer a definitive progeria cure, but it could buy patients more time by improving their health in other ways.

“While Ang2 only has receptors on the endothelial cells, it may have a broader beneficial impact on additional tissue types beyond cardiovascular systems, such as bone and fat tissues, since blood vessels are essential for our body to transport nutrients, oxygen and waste,” said Cao, who started studying progeria during her postdoc in 2005, just two years after the cause of progeria was discovered.

As a next step, Cao plans to conduct a follow-up study in collaboration with a group at the NIH to explore different methods of administering Ang2 to animal models with progeria.

While the work is ongoing, Cao is confident that each new study will bring researchers closer to identifying a cure. “We are getting really close to a cure for progeria,” she said. “Research-wise, we are pushing hard, and I can see the light at the end of the tunnel.”