A study led by researchers in Madrid has uncovered the likely cause of the severe symptoms of atherosclerosis seen in children with the genetic aging disorder Hutchinson-Gilford progeria syndrome.
As reported in The Journal of Clinical Investigation, the research team found that increased activity of two transcriptional activator proteins YAP and TAZ that act together to regulate cell proliferation, organ growth, stress response and differentiation of certain cells likely cause the atherosclerotic symptoms seen in children with this type of progeria.
The investigators created and tested a mouse model of this condition and found that they were able to reverse some of the atherosclerotic symptoms in the mice by inhibiting the YAP/TAZ pathway using verteporfin, a drug used to eliminate abnormal blood vessel formation in some types of eye disease such as wet macular degeneration for which it is already approved by the FDA.
“The results are very encouraging. By targeting the YAP/TAZ pathway, we were able to significantly reduce the progression of atherosclerosis in our Hutchinson-Gilford progeria syndrome mouse model,” said co-lead author Vicente Andrés, leader of the Molecular and Genetic Cardiovascular Pathophysiology group at the CNIC and principal investigator in the Spanish cardiovascular research network, in a press statement.
“While more research is needed, this opens up the possibility of developing new therapies that could one day be used to treat not only Hutchinson-Gilford progeria syndrome but also other age-related cardiovascular diseases.”
Hutchinson-Gilford progeria syndrome is a very rare genetic disorder affecting around 1 in 20 million people. It is caused by a mutation in the LMNA gene that causes abnormal progerin proteins to be produced that cause accelerated aging in those with the condition.
Most people with this type of progeria die before the age of 15 years, usually from some type of heart failure, heart attack of stroke caused by severe atherosclerosis in their arteries.
Andrés and colleagues discovered the cause of this atherosclerosis by using single cell RNA sequencing to closely study the aorta and the endothelial cells lining it in mice with Hutchinson-Gilford progeria syndrome and controls.
“Our findings suggest that the stiffening of the arterial wall and the changes in blood flow patterns in Hutchinson-Gilford progeria syndrome trigger the activation of the YAP/TAZ pathway in endothelial cells. This in turn promotes inflammation and the accumulation of immune cells in the arteries, which accelerates the development of atherosclerosis,” explained first author Ana Barettino, a researcher from the National Centre for Cardiovascular Research in Madrid.
This research is promising and may result in the development of new treatments for people with this rare disease, but the researchers caution that more research is needed before this can become a reality. They also need to better understand how to specifically target the YAP/TAZ pathway in disease-causing cells without damaging healthy tissue.
