Stanford researchers have identified a shared signaling pathway that drives cardiac fibrosis, the scar-tissue buildup that stiffens the heart and weakens its ability to pump. By studying three adenosine receptor subtypes on heart fibroblasts, the team discovered that each normally sends different signals but converges on a single pathway called G-beta-gamma, which activates scar-forming cells.
Drug Screening Reveals Key Compound
Working with collaborators at UCLA, Boston University, MD Anderson Cancer Center, the University of Arizona, and Greenstone Biosciences, the researchers used human induced pluripotent stem cells (iPSCs) to build a drug-screening platform. They tested roughly 4,000 bioactive compounds for their ability to stop fibroblasts from activating and producing scar tissue, while filtering out candidates that harmed heart muscle or blood-vessel cells.
The study identified CGS15943—a compound that inhibits multiple adenosine receptors—as the most promising candidate. Tests in human heart cells, including fibroblasts from cardiomyopathy patients and lab-grown heart tissues, showed it decreased tissue stiffness while enhancing both contraction and relaxation functions.
When given to mice already suffering from heart scarring and weakened function, CGS slowed additional fibrosis and prevented further decline, though it did not eliminate pre-existing scar tissue.
‘Our goal was to create a screening system that could quickly eliminate any substance harmful to the heart, not just those that merely halted scarring,’ explained Hao Zhang, MD, a UCLA assistant professor and co-lead author who began the work at Stanford.
Receptors Converge on a Common Signal
CGS blocks receptors for adenosine, a natural signaling molecule that increases during stress and tissue injury. The study focused on three adenosine receptor subtypes, A1, A2A, and A2B, all found on cardiac fibroblasts.
These receptors belong to the G protein-coupled receptor (GPCR) family, which typically signals through various G-alpha proteins, sometimes producing conflicting effects. However, the team discovered that all three receptors also rely on a shared pathway: the G-beta-gamma subunit, a component often overlooked in GPCR research.
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Blocking one receptor at a time had limited impact on fibroblast activation. Blocking all three together produced a much stronger response. This may explain why earlier studies targeting individual adenosine receptors yielded mixed results.
‘While these adenosine receptors usually work through different G-alpha proteins, we found they were all operating through an unusual route,’ noted Rabindra V. Shivnaraine, PhD, a co-first author. ‘This shared G-beta-gamma signal helps clarify why blocking them collectively had a far greater antifibrotic impact than targeting them individually.’
G-Beta-Gamma Drives Fibrosis in Mice
Shivnaraine completed his postdoctoral training under Brian Kobilka, MD, in Stanford’s Department of Molecular and Cellular Physiology. Kobilka, a study co-author, won the 2012 Nobel Prize in Chemistry for his GPCR research.
The team then investigated whether the G-beta-gamma pathway directly contributes to fibrosis. In a heart injury mouse model, blocking this signal in fibroblasts reduced scarring and improved heart performance.
Additional experiments revealed that G-beta-gamma influences pathways regulating fibroblast activation and gene expression linked to scar formation. The findings imply that disrupting a central hub where multiple disease signals converge could be more effective than addressing each pathway separately.
Implications Beyond the Heart
CGS remains a proof-of-concept research compound, not an approved treatment. Developing it further would require optimization, safety testing, and pharmacokinetic studies.
The team also observed antifibrotic effects in human keloid fibroblasts and a mouse model of skin fibrosis, suggesting the pathway may be relevant to fibrosis in organs beyond the heart. The study, titled “Targeting an atypical G protein-coupled receptor signaling pathway for cardiac fibrosis therapy,” was published in Science.