HINT1 aggravates aortic aneurysm by targeting ITGA6/FAK axis in vascular smooth muscle cells
Yan Zhang, Wencheng Wu, Xuehui Yang, Shanshan Luo, Xiaoqian Wang, Qiang Da, Ke Yan, Lulu Hu, Shixiu Sun, Xiaolong Du, Xiaoqiang Li, Zhijian Han, Feng Chen, Aihua Gu, Liansheng Wang, Zhiren Zhang, Bo Yu, Chenghui Yan, Yaling Han, Yi Han, Liping Xie, Yong Ji
Yan Zhang, Wencheng Wu, Xuehui Yang, Shanshan Luo, Xiaoqian Wang, Qiang Da, Ke Yan, Lulu Hu, Shixiu Sun, Xiaolong Du, Xiaoqiang Li, Zhijian Han, Feng Chen, Aihua Gu, Liansheng Wang, Zhiren Zhang, Bo Yu, Chenghui Yan, Yaling Han, Yi Han, Liping Xie, Yong Ji
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Research Article Cardiology Vascular biology

HINT1 aggravates aortic aneurysm by targeting ITGA6/FAK axis in vascular smooth muscle cells

Abstract

Aortic aneurysm is a high-risk cardiovascular disease without an effective cure. Vascular smooth muscle cell (VSMC) phenotypic switching is a key step in the pathogenesis of aortic aneurysm. Here, we revealed the role of histidine triad nucleotide-binding protein 1 (HINT1) in aortic aneurysm. HINT1 was upregulated both in aortic tissue from patients with aortic aneurysm and angiotensin II–induced aortic aneurysm mice. VSMC-specific HINT1 deletion alleviated aortic aneurysm via preventing VSMC phenotypic switching. With the stimulation of pathological factors, the increased nuclear translocation of HINT1 mediated by nucleoporin 98 promoted the interaction between HINT1 and transcription factor AP-2 α (TFAP2A), further triggered the transcription of integrin α6 (ITGA6) mediated by TFAP2A, and consequently activated the downstream focal adhesion kinase (FAK)/STAT3 signal pathway, leading to aggravation of VSMC phenotypic switching and aortic aneurysm. Importantly, defactinib treatment was demonstrated to limit aortic aneurysm development by inhibiting the FAK signal pathway. Thus, the HINT1/ITGA6/FAK axis emerges as a potential therapeutic strategy in aortic aneurysm.

Authors

Yan Zhang, Wencheng Wu, Xuehui Yang, Shanshan Luo, Xiaoqian Wang, Qiang Da, Ke Yan, Lulu Hu, Shixiu Sun, Xiaolong Du, Xiaoqiang Li, Zhijian Han, Feng Chen, Aihua Gu, Liansheng Wang, Zhiren Zhang, Bo Yu, Chenghui Yan, Yaling Han, Yi Han, Liping Xie, Yong Ji

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Figure 3

ITGA6 is the downstream target of HINT1.

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ITGA6 is the downstream target of HINT1. (A) Kyoto Encyclopedia of Genes...
(A) Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of differentially expressed genes in PDGF-BB–treated MASMCs isolated from the whole aorta of WT and Hint1–/– mice. (B) Venn diagram showing 4 overlapping targets that were all enriched in the related pathways (blue, ECM-receptor interaction; red, regulation of actin cytoskeleton; green, PI3K/AKT signaling pathway; and yellow, focal adhesion) in A. (C) q-PCR analysis of above 4 overlapping targets (Itga6, Itga7, Itga8, and Itgb8) in MASMCs isolated from the whole aortas of WT and Hint1–/– mice and treated with PDGF-BB (20 ng/mL) (n = 6 per group). (D and E) q-PCR (D) and Western blotting (E) analysis of Itga6 in MASMCs isolated from the whole aortas of WT and Hint1–/– mice and treated with PBS or PDGF-BB (20 ng/mL) (n = 6 per group). (F and G) q-PCR (F) and Western blotting (G) analysis of Itga6 in HASMCs transfected with siN or siHINT1 followed by PBS or PDGF-BB (20 ng/mL) stimulation (n = 6 per group). (H–J) Eight-week-old male Apoe–/–/Hint1fl/fl and Apoe–/–/Hint1SMKO mice were infused with saline or Ang II (1,000 ng/kg/min) for 28 days. q-PCR (H) and Western blotting (I) analysis of the levels of Itga6 in aortas. n = 6–8 per group. (J) Representative immunofluorescence staining of ITGA6 expression in abdominal aortas. Scale bar: 20 μm. L, lumen. Statistical analysis was performed by Student’s t test (C) or 1-way ANOVA (D–I). For all statistical plots, the data are presented as mean ± SEM.