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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 6

SLIT3 deficiency inhibits fibroblast biological activity.

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SLIT3 deficiency inhibits fibroblast biological activity.
(A) MTT cell p...
(A) MTT cell proliferation assay. Slit3−/− and WT aortic adventitial fibroblasts were seeded in 96-well plates (10% FBS medium) and treated with PBS or PDGF-BB (100 ng/mL). Absorbance was measured at 560 nm at 0 and 48 hours after treatments (n = 6–14 per group). (B) Floating collagen gel contraction assay. Representative images and area quantification of collagen gel. Slit3−/− and WT lung fibroblasts were seeded in PBS or TGF-β1 (5.0 ng/mL) added to collagen gel (1 mg/mL collagen type I, 0.5% FBS). The final to initial area ratio was determined at 24 hours after floating (n = 3 per group). Scale bars: 5 mm. (C) Scratch wound healing assay. Representative images and migration distance quantification of scratch wound healing. Slit3−/− and WT lung fibroblasts were seeded in 6-well plates (1% FBS medium) and treated with PBS or PDGF-BB (100 ng/mL). The migration distance was determined at 24 hours after scratching (n = 4). Scale bars: 20 μm. (D) Excisional wound healing assay. Representative gross and histological images (hematoxylin and eosin staining) and quantification of wound area in 8-week-old Slit3−/− and WT mice at the day of surgery (day 0) and 15 days (day 15) after surgery (n = 19–21 per group). Scale bars: 1 mm and 700 μm from top to bottom. Data are presented as mean ± SD. In vitro experiments were performed at least 3 times independently. *P < 0.05, **P < 0.01, and ***P < 0.001 vs. WT mice or cells using the unpaired 2-tailed Student’s t test (D) or 2-way ANOVA with 2-stage step-up method of Benjamini, Krieger, and Yekutieli multiple comparisons test (A–C).

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