Translational regulation of SND1 governs endothelial homeostasis during stress
Zhenbo Han, … , Soroush Tahmasebi, Sang-Ging Ong
Zhenbo Han, … , Soroush Tahmasebi, Sang-Ging Ong
Published February 3, 2025
Citation Information: J Clin Invest. 2025;135(3):e168730. https://doi.org/10.1172/JCI168730.
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Research Article Vascular biology Article has an altmetric score of 8

Translational regulation of SND1 governs endothelial homeostasis during stress

Abstract

Translational control shapes the proteome and is particularly important in regulating gene expression under stress. A key source of endothelial stress is treatment with tyrosine kinase inhibitors (TKIs), which lowers cancer mortality but increases cardiovascular mortality. Using a human induced pluripotent stem cell–derived endothelial cell (hiPSC-EC) model of sunitinib-induced vascular dysfunction combined with ribosome profiling, we assessed the role of translational control in hiPSC-ECs in response to stress. We identified staphylococcal nuclease and tudor domain–containing protein 1 (SND1) as a sunitinib-dependent translationally repressed gene. SND1 translational repression was mediated by the mTORC1/4E-BP1 pathway. SND1 inhibition led to endothelial dysfunction, whereas SND1 OE protected against sunitinib-induced endothelial dysfunction. Mechanistically, SND1 transcriptionally regulated UBE2N, an E2-conjugating enzyme that mediates K63-linked ubiquitination. UBE2N along with the E3 ligases RNF8 and RNF168 regulated the DNA damage repair response pathway to mitigate the deleterious effects of sunitinib. In silico analysis of FDA-approved drugs led to the identification of an ACE inhibitor, ramipril, that protected against sunitinib-induced vascular dysfunction in vitro and in vivo, all while preserving the efficacy of cancer therapy. Our study established a central role for translational control of SND1 in sunitinib-induced endothelial dysfunction that could potentially be therapeutically targeted to reduce sunitinib-induced vascular toxicity.

Authors

Zhenbo Han, Gege Yan, Jordan Jousma, Sarath Babu Nukala, Mehdi Amiri, Stephen Kiniry, Negar Tabatabaei, Youjeong Kwon, Sen Zhang, Jalees Rehman, Sandra Pinho, Sang-Bing Ong, Pavel V. Baranov, Soroush Tahmasebi, Sang-Ging Ong

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Figure 6

Identification of ramipril as a candidate compound that protects against sunitinib-induced vascular dysfunction.

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Identification of ramipril as a candidate compound that protects against...
(A) Schematic of in silico drug screening using a Connectivity Map (CMap) approach. (B) Heatmap representing the shSND1-regulated genes (red: 20 most upregulated; blue: 20 most downregulated) obtained from RNA-Seq data. (C) Chemical compound ranking chart based on connectivity score (Norm_cs) and transcriptional activity score (tas). moa, mechanism of action. (D) hiPSC-ECs were treated with drospirenone (250 nM), ramipril (3 μM), or ripasudil (1 μM) along with sunitinib (2 μM) or DMSO for 48 hours. Cell viability was determined using the PrestoBlue cell viability reagent. One-way ANOVA. Data are presented as mean ± SD. ***P < 0.001. n = 9 replicates from the differentiation of 3 individual hiPSC lines. (E) Representative images of wound-healing ability of hiPSC-ECs treated with sunitinib (2 μM) for 48 hours in the presence and absence of drospirenone (250 nM), ramipril (3 μM), or ripasudil (1 μM). Treatment with DMSO was used as control. The yellow lines indicate the edges of the scratch wound. Scale bars: 220 μm. (F and G) hiPSC-ECs were treated with sunitinib (0.25 μM) for 48 hours in the presence and absence of ramipril (3 μM). Endothelial cell function was determined by tube-formation assay. Scale bar: 100 μm. One-way ANOVA. Data are presented as mean ± SD. *P < 0.05, **P < 0.01. n = 6 replicates from the differentiation of 3 individual hiPSC lines.