In pulmonary hypertension and certain forms of congenital heart disease, ventricular pressure overload manifests at birth and is an obligate hemodynamic abnormality that stimulates myocardial fibrosis which leads to ventricular dysfunction and poor clinical outcomes. Thus, an attractive strategy is to attenuate the myocardial fibrosis to help preserve ventricular function. Here, by analyzing RNA-sequencing databases and comparing the transcript and protein levels of fibrillar collagen in wild-type and global knockout mice, we found that SLIT3 was predominantly present in fibrillar collagen-producing cells and that SLIT3 deficiency attenuated collagen production in the heart and other non-neuronal tissues. We then performed transverse aortic constriction or pulmonary artery banding in wild-type and knockout mice to induce left and right ventricular pressure overload, respectively. We discovered that SLIT3 deficiency abrogates fibrotic and hypertrophic changes and promotes long-term ventricular function and overall survival in both left and right ventricular pressure overload. Furthermore, we found that SLIT3 stimulated fibroblast activity and fibrillar collagen production, which coincided with the transcription and nuclear localization of the mechanotransducer YAP1. These results indicate that SLIT3 is important for regulating fibroblast activity and fibrillar collagen synthesis in an autocrine manner, making it a potential therapeutic target for fibrotic diseases, especially myocardial fibrosis and adverse remodeling induced by persistent afterload elevation.
Lianghui Gong, Shuyun Wang, Li Shen, Catherine Liu, Mena Shenouda, Baolei Li, Xiaoxiao Liu, John Shaw, Alan Wineman, Yifeng Yang, Dingding Xiong, Anne Eichmann, Sylvia M. Evans, Stephen J. Weiss, Ming-Sing Si