Pathway discovered that could yield therapies to prevent hearts turning to “bone”

In the Rolling Stones’ lyrics having a “Heart of Stone” protected you from heartbreak. But over a million Americans are developing hearts of bone and it could kill them.

CIRM-funded researchers at the Gladstone Institutes think they have uncovered the path to this destructive hardening of the heart and that could lead to therapies to stop the damage. In particular, they looked at heart valves and why in some people the cells in those valves start acting like bone and produce calcium that causes them to get rigid and loose their proper function.

Valve cells come from a family of cells called endothelial cells that includes the lining of blood vessels, which are also prone to inappropriate production of calcium and hardening. So, the findings could have much broader implication for heart disease and therapy.

A mutation in the Notch1 gene makes cells react inappropriately to the sheer stress caused by blood flow. Team found BMP, SFB and MMP genes control this.

A mutation in the Notch1 gene makes cells react inappropriately to the sheer stress caused by blood flow. Team found BMP, SFB and MMP genes control this.

Led by senior author Deepak Srivastava, the team used stem cell technology to create endothelial cells from patients with genetic calcific aortic valve disease (CAVD) and from normal individuals. They then pushed those cells to mature into valve cells in the lab and monitored which genes were turned on or off during the process, comparing the disease carrying and normal cells.

They built on a previous discovery of Srivastava, who found that a defect in the gene NOTCH1 can cause valve birth defects and CAVD. Searching hundreds of genes and gene switches they came upon three genes that appear to be master regulators of the path that leads cells to overproduce calcium. In a press release from the Gladstone, he said:

“Identifying these master regulators is a big step in treating CAVD, not just in people with the NOTCH1 mutation, but also in other patients who experience calcification in their valves and arteries. Now that we know how calcification happens and what the key nodes are, we know what genes to look for that might be mutated in other related forms of cardiovascular disease.”

The release noted that the research team is now screening for drugs that can act on this gene network. Srivastava’s main focus has been on congenital pediatric heart disease. He discusses that research in three brief videos that include the story of one very special young patient.

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