Many elastic tissues harden with age in part due to calcification, an increased deposition of calcium between cells. In the cardiovascular system this is eventually fatal, as elasticity in blood vessels and the heart are essential to proper function. The usual focus for discussion here is the stiffening of blood vessel walls through this and other mechanisms, causing hypertension and all its attendant consequences, but heart tissue also stiffens and calcifies:
Calcific aortic valve disease (CAVD) is the third leading cause of heart disease. In CAVD, which can develop with age, heart valves begin to produce calcium, causing them to harden like bone. Scientists have long known that blood flow in the heart plays a role in the calcification of valves and arteries, but they did not understand how. In a new study, investigators reveal the chain of events that cause healthy valves to become bone-like. The researchers had previously discovered that disruption of one of two copies of a master gene called NOTCH1 can cause valve birth defects and CAVD. In the current study, the researchers report that NOTCH1 acts like a sensor on the endothelial cell - the cells that line the valve and vessels - detecting blood flow outside of the cell and transmitting information to a network of genes inside the cell. Activation of NOTCH1 by blood flow causes a domino effect, triggering numerous other genes in the network to turn on or off, resulting in suppression of inflammation and calcification. However, if this process is disrupted by a decrease in NOTCH1, the cells become confused and start to act like bone cells, laying down calcium and leading to a deadly hardening of the valve.
The scientists used stem cell technology to make large amounts of endothelial cells from patients with CAVD, comparing them to healthy cells and mapping their genetic and epigenetic changes as they developed into valve cells. The researchers used the power of gene sequencing and clever computational methods to uncover the "source code" for human endothelial cells and learn how that code is disturbed in human disease. "By understanding the gene networks that get disrupted in CAVD, we can pinpoint what we need to fix and find new therapeutics to correct the disease process." Sifting through this mountain of data, the scientists found three key genes that were altered by the NOTCH1 mutation and also acted as master regulators, turning off the critical pathways that normally prevent inflammation and calcification. Remarkably, when the researchers manipulated the activity of these three genes, almost all of the other genes in the network were corrected, pointing to novel therapeutic targets for CAVD. The scientists are now screening for drugs that restore the gene network to its normal state.