Investigators at Nationwide Children’s Hospital and the University of Texas Southwestern Medical Center have demonstrated how a gene responsible for cell differentiation and its signaling pathway is linked to calcium deposits developing on the aortic valve in the human heart. The study, appearing in PLoS One provides insight into how the most common form of valvular heart disease may develop.
In aortic valve calcification, the most common form of valvular heart disease, calcium deposits form on the heart’s aortic valve, which can cause narrowing at the valve’s opening, reducing blood flow. Physicians agree that calcific aortic valve disease (CAVD) is influenced by genetic and environmental factors, but the underlying mechanisms that lead to its development remain unclear.
“Mutations in a receptor known as NOTCH1 have been reported in families with bicuspid aortic valve and CAVD,” said Vidu Garg, MD, principal investigator in the Center for Cardiovascular and Pulmonary Research at The Research Institute at Nationwide Children’s Hospital and the lead study author. “The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood.”
To investigate the molecular changes that occur when Notch signaling is inhibited in the aortic valve, Dr. Garg and colleagues examined diseased human aortic valves, provided by Cincinnati Children’s, and heart valve cells from two animal models in which Notch signaling was inhibited.
They found that NOTCH1 expression was decreased in areas of calcium deposition in diseased human aortic valves. When Notch signaling was inhibited in the animal heart valve cells, expression of Sox9, a key transcription required for normal valve development, was downregulated. Loss of Sox9 expression has been shown to be associated with aortic valve calcification. They also found that over-expression of Sox9 reduces the calcification that occurs with Notch inhibition.
“Our study demonstrates that Notch1 and its downstream mediators are expressed in the adult aortic valve and loss of Notch signaling is associated with areas of calcification in human aortic valves,” said Dr. Garg. “Our findings suggest that Notch regulates calcification of aortic valve cells in a molecular pathway mediated by Sox9.”
Dr. Garg says that further studies into the Notch 1-Sox9 molecular pathway and its role in maintaining a healthy heart will lead to further understanding of CAVD that could lead to new therapies.
Acharya A, Hans CP, Koenig SN, Nichols HA, Galindo CL, Garner HR, Merrill WH, Hinton RB, Garg V. Inhibitory role of notch1 in calcific aortic valve disease. PLoS One. 2011;6(11):e27743. Epub 2011 Nov 16.