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SLIT3 deficiency attenuates pressure overload–induced cardiac fibrosis and remodeling
Lianghui Gong, … , Stephen J. Weiss, Ming-Sing Si
Lianghui Gong, … , Stephen J. Weiss, Ming-Sing Si
Published May 19, 2020
Citation Information: JCI Insight. 2020;5(12):e136852. https://doi.org/10.1172/jci.insight.136852.
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Research Article Cardiology Cell biology

SLIT3 deficiency attenuates pressure overload–induced cardiac fibrosis and remodeling

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Abstract

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.

Authors

Lianghui Gong, Shuyun Wang, Li Shen, Catherine Liu, Mena Shenouda, Baolei Li, Xiaoxiao Liu, John A. Shaw, Alan L. Wineman, Yifeng Yang, Dingding Xiong, Anne Eichmann, Sylvia M. Evans, Stephen J. Weiss, Ming-Sing Si

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Figure 1

SLIT3 is present at high levels in fibrillar collagen–producing cells.

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SLIT3 is present at high levels in fibrillar collagen–producing cells.
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(A) Linear regression analysis between the transcript levels of SLIT3 and COL1A1, SLIT3 and COL3A1, and ROBO1 and COL1A1 across 512 cell lines from the FANTOM5 project (28). TPM, transcripts per million. (B) Single-cell transcriptome data from the Tabula Muris project (29), with t-distributed stochastic neighbor embedding plot of all cells collected by FACS, overlaid with the predominant cell type composing each cluster (n = 44,949 individual cells from 20 mouse organs). The clusters of cells expressing Slit3, Col1a1, and Robo1. (C) Transcript levels of Slit3, Col1a1, and Robo1 in cardiac fibroblasts, left ventricle, freshly isolated cardiomyocytes, aortic adventitial fibroblasts, lung fibroblasts, aortic vascular smooth muscle cells (VSMC), aorta media, and aorta adventitia from WT mice. Samples taken directly from or isolated from living tissue are marked blue and samples of purified and cultured cells are marked red on panels. Each data point represents tissue/cells obtained from a single animal. (D) Confocal immunofluorescence images of mouse aortic adventitial fibroblasts stained with SLIT3 (shown in green), ROBO1 (shown in green), and DAPI (shown in blue) (n = 2). Scale bars: 50 μm. *P < 0.05, **P < 0.01, and ***P < 0.001 using 1-way ANOVA with Tamhane T2 multiple comparisons test (C).

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