DA-GIP suppresses cardiac fibroblast activity through Akt-dependent eNOS activation and subsequent NO production, thereby improving cardiac remodeling and function in experimental heart failure.
DA-GIP treatment significantly reduced migratory activity of human cardiac fibroblasts compared to control cells.
DA-GIP reduced expression of key pro-fibrotic proteins in human cardiac fibroblasts.
DA-GIP increased nitric oxide production and promoted activation of eNOS and Akt in cardiac fibroblasts.
Akt signaling was required for DA-GIP-induced eNOS activation in cardiac fibroblasts.
Nitric oxide synthase inhibition attenuated the antifibrotic effect of DA-GIP.
DA-GIP administration reduced myocardial fibrosis, chamber dilatation, and systolic dysfunction in heart failure rats.
This research suggests that activating the receptor for a hormone called glucose-dependent insulinotropic polypeptide (GIP) — using a drug compound called DA-GIP — can reduce harmful scarring in heart tissue and improve heart function. In laboratory experiments with human heart cells called cardiac fibroblasts (the cells primarily responsible for producing scar tissue), DA-GIP reduced the cells' ability to migrate and lowered their production of proteins that build up scar tissue. The researchers found this happened through a specific chain of molecular signals: DA-GIP activated a protein called Akt, which then activated an enzyme called eNOS, which produced nitric oxide — a signaling molecule that reduced the fibroblasts' scarring activity. When researchers blocked any step in this chain, the antifibrotic effect was diminished, confirming the pathway. In animal experiments, rats with heart failure induced by a drug called isoproterenol were treated with DA-GIP injections twice daily for two weeks. Compared to untreated heart failure rats, the DA-GIP-treated animals showed less myocardial scarring, less enlargement of the heart chambers, and better heart pumping function as measured by echocardiography (ultrasound imaging of the heart). This research matters because cardiac fibrosis — the buildup of scar tissue in the heart — is a major contributor to heart failure, a condition affecting millions of people worldwide, and current treatments have limited ability to reverse this scarring process. GIP is already of clinical interest because related hormones (GLP-1) are the basis of widely used diabetes and weight-loss medications. This study suggests that targeting the GIP receptor specifically may offer a new therapeutic approach to reducing cardiac fibrosis and improving heart failure outcomes, though further research in humans would be needed to confirm these findings.
Lee T, Lee T, Higa S, Kao Y, Chen Y. (2026). Glucose-dependent insulinotropic polypeptide receptor agonism improves heart failure with antifibrosis through Akt-dependent nitric oxide signaling.. Journal of biomedical science. https://doi.org/10.1186/s12929-026-01288-1