Work

Beneficial Effects of Chymase Inhibition on Cardiac Diastolic Function and Remodeling Induced by Chronic Angiotensin II Stimulation

Year: 2025

Type: article

Abstract: In addition to its role in angiotensin II (Ang II) production, chymase exhibits various functions, including activation of latent transforming growth factor beta 1 (TGF-β1) and pro-matrix metalloproteinases (MMPs). However, the extent to which these Ang II-independent functions contribute to pathological conditions remains unclear. In this study, we investigated the Ang II-independent roles of chymase in cardiac remodeling and dysfunction. Eighteen male Syrian hamsters, aged 6 weeks and weighing 90-110 g, were used. Exogenous Ang II was administered to a hamster model that mirrors the human chymase-dependent Ang II production pathway, via subcutaneous osmotic mini pumps (2 mg/kg/day) for 4 weeks. A chymase-specific inhibitor, TY-51469 (10 mg/kg/day), was given daily starting 1 day after commencement of Ang II infusion. Evaluation showed that while systolic blood pressure increased significantly, only diastolic dysfunction developed over time. Ang II treatment led to elevated cardiac expression of chymase, TGF-β1, and MMP-2, and increased the number of chymase-positive mast cells, resulting in notable cardiac hypertrophy and fibrosis. TY-51469 effectively suppressed these molecular changes and improved both cardiac structure and diastolic dysfunction, despite continued Ang II exposure. These results suggest that chymase promotes cardiac remodeling and dysfunction not only through Ang II generation but also by activating profibrotic and matrix-degrading factors, such as TGF-β1 and MMP-2.

Source: International Journal of Molecular Sciences

DOI: 10.3390/ijms26178236

Authors: Shiguma Taniguchi, Denan Jin, Hirofumi Morihara, Shunichi Yokoe, Kazumasa Moriwaki, Shinji Takai

Institution: Osaka Medical and Pharmaceutical University

Language: English

Topic: Renin-Angiotensin System Studies

Subfield: Cardiology and Cardiovascular Medicine

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: gold

Estimated APC paid: $3,499