Section of Pediatric Cardiovascular Surgery, Department of Cardiac Surgery, Michigan Medicine, University of Michigan, Ann Arbor, Michigan, USA.
Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.
JCI Insight. 2020 Jun 18;5(12):136852. doi: 10.1172/jci.insight.136852.
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 WT and global-knockout mice, we found that slit guidance ligand 3 (SLIT3) was present predominantly in fibrillar collagen-producing cells and that SLIT3 deficiency attenuated collagen production in the heart and other nonneuronal tissues. We then performed transverse aortic constriction or pulmonary artery banding to induce left and right ventricular pressure overload, respectively, in WT and knockout mice. We discovered that SLIT3 deficiency abrogated fibrotic and hypertrophic changes and promoted 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 yes-associated protein 1. 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.
在肺动脉高压和某些先天性心脏病中，心室压力超负荷在出生时就表现出来，这是一种强制性的血流动力学异常，会刺激心肌纤维化，导致心室功能障碍和不良的临床结局。因此，一种有吸引力的策略是减轻心肌纤维化，以帮助维持心室功能。在这里，我们通过分析 RNA 测序数据库并比较 WT 和全局敲除小鼠的纤维胶原的转录物和蛋白水平，发现 SLIT3 主要存在于产生纤维胶原的细胞中，SLIT3 缺失可减轻心脏和其他非神经元组织中的胶原产生。然后，我们在 WT 和敲除小鼠中进行了升主动脉缩窄或肺动脉缩窄，分别诱导左心室和右心室压力超负荷。我们发现，SLIT3 缺失消除了纤维化和肥大改变，并促进了左心室和右心室压力超负荷的长期心室功能和整体存活率。此外，我们发现 SLIT3 刺激成纤维细胞活性和纤维胶原产生，这与机械转导物 yes 相关蛋白 1 的转录和核定位相吻合。这些结果表明，SLIT3 以自分泌方式调节成纤维细胞活性和纤维胶原合成，使其成为纤维化疾病的潜在治疗靶点，特别是持续性后负荷升高引起的心肌纤维化和不良重构。
