SLC44A2 regulates vascular smooth muscle cell phenotypic switching and aortic aneurysm
Tianyu Song, … , Liping Xie, Yong Ji
Tianyu Song, … , Liping Xie, Yong Ji
Published June 25, 2024
Citation Information: J Clin Invest. 2024;134(16):e173690. https://doi.org/10.1172/JCI173690.
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Research Article Vascular biology

SLC44A2 regulates vascular smooth muscle cell phenotypic switching and aortic aneurysm

Abstract

Aortic aneurysm is a life-threatening disease with limited interventions that is closely related to vascular smooth muscle cell (VSMC) phenotypic switching. SLC44A2, a member of the solute carrier series 44 (SLC44) family, remains undercharacterized in the context of cardiovascular diseases. Venn diagram analysis based on microarray and single-cell RNA sequencing identified SLC44A2 as a major regulator of VSMC phenotypic switching in aortic aneurysm. Screening for Slc44a2 among aortic cell lineages demonstrated its predominant location in VSMCs. Elevated levels of SLC44A2 were evident in the aorta of both patients with abdominal aortic aneurysm and angiotensin II–infused (Ang II–infused) Apoe–/– mice. In vitro, SLC44A2 silencing promoted VSMCs toward a synthetic phenotype, while SLC44A2 overexpression attenuated VSMC phenotypic switching. VSMC-specific SLC44A2-knockout mice were more susceptible to aortic aneurysm under Ang II infusion, while SLC44A2 overexpression showed protective effects. Mechanistically, SLC44A2’s interaction with NRP1 and ITGB3 activates TGF-β/SMAD signaling, thereby promoting contractile gene expression. Elevated SLC44A2 in aortic aneurysm is associated with upregulated runt-related transcription factor 1 (RUNX1). Furthermore, low-dose lenalidomide (LEN; 20 mg/kg/day) suppressed aortic aneurysm progression by enhancing SLC44A2 expression. These findings reveal that the SLC44A2-NRP1-ITGB3 complex is a major regulator of VSMC phenotypic switching and provide a potential therapeutic approach (LEN) for aortic aneurysm treatment.

Authors

Tianyu Song, Shuang Zhao, Shanshan Luo, Chuansheng Chen, Xingeng Liu, Xiaoqi Wu, Zhongxu Sun, Jiawei Cao, Ziyu Wang, Yineng Wang, Bo Yu, Zhiren Zhang, Xiaolong Du, Xiaoqiang Li, Zhijian Han, Hongshan Chen, Feng Chen, Liansheng Wang, Hong Wang, Kangyun Sun, Yi Han, Liping Xie, Yong Ji

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Figure 7

The transcription of SLC44A2 is regulated by RUNX1.

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The transcription of SLC44A2 is regulated by RUNX1. (A) Prediction of SL...
(A) Prediction of SLC44A2 promoter–binding transcription factors by JASPAR (https://jaspar.elixir.no/) and with the upstream 2,000 bp to downstream 100 bp region of SLC44A2 gene transcription initiation site set as the promoter region. Venn diagram of DEGs in murine (GSE17901 and GSE51229) and human (GSE7084) aortic aneurysm samples relative to normal controls from the NCBI GEO database. AA, aortic aneurysm; PPE, porcine pancreatic elastase. (B) HASMCs were transfected with siRUNX1 or siNC, and then treated with Ang II (1 μM, 24 hours). The levels of SLC44A2 and RUNX1 were detected by Western blotting. n = 5. (C) Western blot analysis of RUNX1 in the aortas of non-AAA and AAA individuals. n = 6. (D) RUNX1 mRNA level in the aortas of non-AAA and AAA individuals was detected by qRT-PCR. n = 6. (E) Relative luciferase activity in HEK293 cells transfected with luciferase reporter constructs containing SLC44A2 promoter truncations or its mutants along with pRL-TK (internal control plasmid) followed by transfection with RUNX1-encoding plasmid. n = 5. Differences were analyzed by 1-way ANOVA followed by Tukey’s multiple-comparison test (B), unpaired, 2-tailed Student’s t test (C and D), or unpaired, 2-tailed Student’s t test or Welch’s t test (E).