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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

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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 7

Ramipril alleviates sunitinib-induced vascular dysfunction without compromising its antitumor efficacy in vivo.

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Ramipril alleviates sunitinib-induced vascular dysfunction without compr...
Orthotopic tumors were induced via injection of 786-O-Fluc cells into right kidney (day 0). The indicated drugs or vehicle were administered via oral gavage once daily from day 16 to day 37. n = 6 mice per group. (A) Representative BLIs of nude mice. (B) Tumor growth was monitored weekly by BLI and measured as photons/s. Two-way ANOVA. Data are presented as mean ± SD. ***P < 0.001. n = 6 per group. Calculated tumor volume (C) and tumor weight (D) in each group on day 45 after tumor xenograft. n = 6 per group. One-way ANOVA. Data are presented as mean ± SD. **P < 0.01 ***P < 0.001. (E and F) Immunohistochemical staining of Ki-67 in tumors. Scale bar: 50 μm. One-way ANOVA. Data are presented as mean ± SD. ***P < 0.001. n = 6 in each group. (G) Representative ultrasound tracings of dilated (induced with 2.5% isoflurane) and basal (with 1% isoflurane) coronary flow after 21 days of treatment with sunitinib (40 mg/kg/d) in the presence and absence of ramipril (10 mg/kg/d). (H) Quantification of coronary flow reserve (CFR) (dilated/basal flow) in sunitinib-treated mice in the presence and absence of ramipril and corresponding vehicle-treated mice. One-way ANOVA. Data are presented as mean ± SD. *P < 0.05, **P < 0.01. Ramipril group: n = 4. Other groups: n = 5 each. (I) Quantification of CD31/53BP1 staining in heart sections of xenografted nude mice (day 45 after tumor xenograft). One-way ANOVA. Data are presented as mean ± SD. ***P < 0.001. Vehicle: n = 5. Sunitinib: n = 4. Ramipril: n = 5. Sunitinib+ramipril: n = 4. (J) Quantification of CD31/γ-H2AX staining in heart sections of xenografted nude mice (day 45 after tumor xenograft). One-way ANOVA. Data are presented as mean ± SD. *P < 0.05, ***P < 0.001. Sunitinib+ramipril group: n = 5. Other groups: n = 6 each. (K and L) Immunoblot analysis revealed that ramipril was unable to reverse sunitinib’s inhibition of SND1 in isolated MCECs (21 days after drug treatment). One-way ANOVA. Data are presented as mean ± SD. ***P < 0.001. n = 6.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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