Pleiotropic role of GAS6 in cardioprotection against ischemia-reperfusion injury

• Published in: Journal of advanced research 2024-04
• Main Authors: Lu, Chenxi, Song, Yanbin, Wu, Xiaopeng, Lei, Wangrui, Chen, Junmin, Zhang, Xin, Liu, Qiong, Deng, Chao, Liang, Zhenxing, Chen, Ying, Ren, Jun, Yang, Yang
• Format: Article
• Language: English
• Subjects: Axl; Catechin; Drug screening; GAS6; Myocardial ischemia–reperfusion injury; SIRT1
• ISSN: 2090-1232; 2090-1224
• DOI: 10.1016/j.jare.2024.04.020

[Display omitted] •GAS6, Axl, and SIRT1 expression levels were decreased in mice subjected to IR injury.•GAS6/Axl-mediated signaling machinery protects against myocardial IR injury likely through inhibition of mitochondrial injury, oxidative stress, and apoptosis.•SIRT1 serves as a downstream effector for GAS6/Axl-initiated myocardial benefits.•Cian, screened from natural product library, possesses potent cardioprotection efficacy via GAS6 activation.•These observations molecularly define a feature of GAS6 that protects against myocardial IR injury. Myocardial ischemia–reperfusion (IR) injury is a common medical issue contributing to the onset and progression of ischemic heart diseases (IHD). Growth arrest-specific gene 6 (GAS6), a vitamin K-dependent secretory protein, promotes cell proliferation and inhibits inflammation and apoptosis through binding with Tyro3, Axl, and Mertk (TAM) receptors. Our study aimed to examine the effect of GAS6 pathways activation as a potential new treatment in myocardial IR injury. Gain- and loss-of-function experiments were utilized to determine the roles of GAS6 in the pathological processes of myocardial IR injury. Our results revealed down-regulated levels of GAS6, Axl, and SIRT1 in murine hearts subjected to IR injury, and cardiomyocytes challenged with hypoxia reoxygenation (HR) injury. GAS6 overexpression significantly improved cardiac dysfunction in mice subjected to myocardial IR injury, accompanied by reconciled mitochondrial dysfunction, oxidative stress, and apoptosis. In vitro experiments also observed a protective effect of GAS6 in cardiomyocytes. SIRT1 was found to function as a downstream regulator for GAS6/Axl signaling axis. Through screening a natural product library, a polyphenol natural compound catechin was identified to exhibit a protective effect by turning on GAS6/Axl-SIRT1 cascade. Together, our findings indicate that GAS6 emerges as a potential novel target in the management of myocardial IR injury and other related anomalies.