Matrine attenuates pathological cardiac fibrosis via RPS5/p38 in mice

• Published in: Acta pharmacologica Sinica Vol. 42; no. 4; pp. 573 - 584
• Main Authors: Zhang, Xin, Hu, Can, Zhang, Ning, Wei, Wen-ying, Li, Ling-li, Wu, Hai-ming, Ma, Zhen-guo, Tang, Qi-zhu
• Format: Journal Article
• Language: English
• Published: Singapore Springer Singapore 01.04.2021; Nature Publishing Group
• Subjects: Alkaloids - therapeutic use; Animals; Aorta; Apoptosis; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cardiomyocytes; Cardiomyopathies - chemically induced; Cardiomyopathies - drug therapy; Cardiotonic Agents - therapeutic use; Cardiovascular diseases; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Transdifferentiation - drug effects; Collagen; Congestive heart failure; Coronary vessels; Doxorubicin; Fibroblasts; Fibroblasts - drug effects; Fibrosis; Fibrosis - chemically induced; Fibrosis - drug therapy; Growth factors; Heart; Heart - drug effects; Immunology; Internal Medicine; Isoproterenol; Kinases; Laboratory animals; Male; MAP Kinase Signaling System - drug effects; Matrines; Medical Microbiology; Mice; Mice, Inbred C57BL; Oxidative stress; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - metabolism; Pharmacology/Toxicology; Proteins; Quinolizines - therapeutic use; Ribosomal protein S5; Ribosomal Proteins - metabolism; Surgery; Up-Regulation - drug effects; Vaccine; ribosomal protein S5; matrine; p38; cardiac fibrosis
• DOI: 10.1038/s41401-020-0473-8
• ISSN: 1671-4083; 1745-7254

Pathological cardiac fibrosis is a common feature in multiple cardiovascular diseases that contributes to the occurrence of heart failure and life-threatening arrhythmias. Our previous study demonstrated that matrine could attenuate doxorubicin-induced oxidative stress and cardiomyocyte apoptosis. In this study, we investigated the effect of matrine on cardiac fibrosis. Mice received aortic banding (AB) operation or continuous injection of isoprenaline (ISO) to generate pathological cardiac fibrosis and then were exposed to matrine lavage (200 mg·kg −1 ·d −1 ) or an equal volume of vehicle as the control. We found that matrine lavage significantly attenuated AB or ISO-induced fibrotic remodeling and cardiac dysfunction. We also showed that matrine (200 μmol/L) significantly inhibited the proliferation, migration, collagen production, and phenotypic transdifferentiation of cardiac fibroblasts. Mechanistically, matrine suppressed p38 activation in vivo and in vitro, and overexpression of constitutively active p38 completely abolished the protective effects of matrine. We also demonstrated that ribosomal protein S5 (RPS5) upregulation was responsible for matrine-mediated inhibition on p38 and fibrogenesis. More importantly, matrine was capable of ameliorating preexisting cardiac fibrosis in mice. In conclusion, matrine treatment attenuates cardiac fibrosis by regulating RPS5/p38 signaling in mice, and it might be a promising therapeutic agent for treating pathological cardiac fibrosis.