Journal Article Epublish
PubMed: 42675474 DOI: 10.1186/s12929-026-01288-1
Glucose-dependent insulinotropic polypeptide receptor agonism improves heart failure with antifibrosis through Akt-dependent nitric oxide signaling.
J Biomed Sci 33(1)
Authors: Ting-Wei Lee, Ting-I Lee, Satoshi Higa, Yu-Hsun Kao, Yi-Jen Chen
Affiliations
- Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan.
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Wan Fang Hospital, Taipei Medical University, Taipei, 11696, Taiwan.
- Cardiac Electrophysiology and Pacing Laboratory, Division of Cardiovascular Medicine, Makiminato Central Hospital, Makiminato, Urasoe, Okinawa, 901-2131, Japan.
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, No.250, Wuxing Street, Taipei, 11031, Taiwan.
- Department of Medical Education and Research, Wan Fang Hospital, Taipei Medical University, Taipei, 11696, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, No.250, Wuxing Street, Taipei, 11031, Taiwan.
- Cardiovascular Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, 11696, Taiwan.
Abstract
BACKGROUND
Cardiac fibrosis is a pathological remodeling process that contributes to the development and progression of heart failure. Although glucose-dependent insulinotropic polypeptide (GIP) may exert antifibrotic effects, how GIP receptor activation regulates cardiac fibrogenesis and modulates cardiac function in heart failure remains unclear. This study investigated whether GIP receptor agonism suppresses cardiac fibroblast activity and improves heart failure and explored the underlying mechanisms by using cellular and animal models.
METHODS
Human cardiac fibroblasts were treated with [D-Ala 2]GIP (DA-GIP; 10, 100, or 300 nM) for 24 h or left untreated (control). Fibroblast migration, collagen production, and intracellular signaling were examined using wound healing, immunoblotting, enzyme-linked immunosorbent, and fluorometric assays. Cardiac structure, function, and fibrosis were assessed through echocardiography and Masson's trichrome staining in rats with isoproterenol-induced heart failure with and without DA-GIP (24 nM/kg, twice daily for 2 weeks) administration.
RESULTS
Compared with control cells, DA-GIP (300 nM)-treated cardiac fibroblasts exhibited a significantly lower migratory activity and reduced expression levels of pro-collagen IA1, pro-collagen III, and transforming growth factor-β1 proteins. Additionally, DA-GIP increased nitric oxide (NO) production and promoted endothelial NO synthase (eNOS) and protein kinase B (Akt) activation in cardiac fibroblasts. Notably, Akt inhibition blocked DA-GIP-induced eNOS activation, and treatment with N ω-nitro-L-arginine methyl ester (a NO synthase inhibitor, 100 μM) attenuated the antifibrotic effect of DA-GIP. In heart failure rats, DA-GIP reduced myocardial fibrosis, chamber dilatation, and systolic dysfunction.
CONCLUSIONS
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.
MeSH
Arginine, Fibrosis, Heart Failure, Heart, Collagen, Fibroblasts