Three receptors that drive cardiac scarring converge on a common pathway, study finds

Three receptors that drive fibrosis, which creates scar tissue in the heart, converge on a common signaling pathway, researchers have found. Blocking all three at once had a much greater antifibrotic effect than blocking them individually, according to the study.

According to Aju Life Science on the 25th (local time), a team at the Stanford Cardiovascular Institute found that three types of adenosine receptors (A1, A2A and A2B) on the surface of cardiac fibroblasts promote fibrosis through a common pathway.

Cardiac fibrosis occurs in several heart diseases and worsens heart failure, but no approved treatments directly target the scarring process.

The team screened about 4,000 bioactive compounds using human induced pluripotent stem cells (iPSCs). The goal was to find compounds that prevent cardiac fibroblasts from activating and becoming scar-forming cells.

A compound that blocks multiple adenosine receptors, CGS15943 (CGS), emerged as a promising candidate. CGS’s antifibrotic effects were confirmed in human cardiac fibroblasts, cells from patients with cardiomyopathy and 3D human heart tissue. In the 3D tissue, stiffness decreased and contraction and relaxation improved.

In mice with established cardiac fibrosis and impaired function, CGS slowed further scar formation and functional decline. However, it did not remove scar tissue that had already formed.

Adenosine receptors belong to the G protein-coupled receptor (GPCR) family and normally send distinct signals through different G-alpha proteins. However, the team found that all three receptors also converge on a common signal called G-beta-gamma.

Blocking the receptors one at a time had a limited effect on suppressing fibroblast activation, but blocking all three simultaneously produced a much stronger response. Ravindra Shivnarain, a co-first author of the study and a researcher at the Stanford Cardiovascular Institute, said, “This common signal explains why blocking the receptors together has a much greater antifibrotic effect.”

The team also directly tested whether G-beta-gamma signaling itself causes fibrosis. In a mouse model of heart injury, selectively blocking this signal in fibroblasts reduced cardiac fibrosis and improved function.

The team said targeting a common point where signals from multiple diseases converge may be more effective than blocking individual signals. However, CGS is a research compound used for proof of concept, and optimization and safety and pharmacokinetic studies are needed before it could become a treatment.

The findings were published in the journal Science.