Pro-Collagen Pathway Regulated by MAS and CTGF May Promote Heart Failure

A new Cleveland Clinic Lerner Research Institute collaboration has demonstrated in human heart cells that increased expression of pro-collagen genes may lead to cardiac fibrosis and, eventually, heart failure. The findings were published in PLoS One.

The researchers, led by the lab of Sadashiva Karnik, PhD, Department of Molecular Cardiology, studied left ventricle tissue samples from heart donors and patients undergoing heart transplantation at Cleveland Clinic.

After comparing the cardiac tissue samples and conducting a series of experiments using drugs to stimulate or silence specific cellular pathways, the researchers found that levels of two proteins — MAS and connective tissue growth factor (CTGF) — were significantly higher in patients with heart failure than in individuals with healthy hearts, and that levels of the proteins were associated with one another. The researchers also found higher levels of collagen genes in the heart failure tissue.

It is widely accepted that MAS, a G protein-coupled receptor, is associated with heart function, although researchers disagree about whether it’s protective or a risk factor for heart disease. CTGF, on the other hand, is known to regulate collagen synthesis and cardiac fibroblast proliferation, which can lead to abnormal changes in the size, shape or structure of the heart. These findings suggest that MAS and CTGF may act together to control pro-collagen expression.

Through a series of protein analyses, researchers in the Karnik lab confirmed their hypothesis. They showed that when activated, the MAS receptor promotes phosphorylation of extracellular signal-related kinases 1 and 2 (ERK1/2), which directly mediates CTGF expression.

“Our data suggest that MAS and CTGF work together to control pro-collagen expression,” Dr. Karnik says. “We believe that when these proteins are overexpressed, possibly due to a genetic variant, collagen production goes unchecked and leads to cardiac fibrosis, which makes it more difficult for the heart to pump.”

While additional research is needed, he adds, the discovery that CTFG expression is downregulated by a novel experimental inhibitor of MAS makes the MAS/CTGF/collagen pathway an ideal target for future heart failure pharmacotherapies.

The study was supported by grants from the National Heart, Lung, and Blood Institute.