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 1

Upregulation of HINT1 correlates with aortic aneurysm.

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Upregulation of HINT1 correlates with aortic aneurysm. (A) Differentiall...
(A) Differentially expressed genes/proteins were identified from aortic tissue of aortic aneurysm patients and controls in 3 databases (green, GSE57691; blue, GSE26155; and red, PXD03229). Venn diagram showing the comparison among the 3 datasets identified 15 overlapping targets. (B and C) Western blotting (B) and q-PCR (C) analysis of HINT1 expression in aorta samples from aortic aneurysm patients and normal aorta samples from donors (n = 6 per group). (D) Representative immunofluorescence images of α-SMA and HINT1 in aortic samples from aortic aneurysm patients and nonaortic aneurysm controls. Red, HINT1; green, α-SMA; blue, DAPI; L, lumen. Scale bars: 50 μm. (E and F) Eight-week-old male Apoe–/– mice were infused with saline or Ang II (1,000 ng/kg/min) for 28 days. Western blotting (E) and q-PCR (F) analysis of HINT1 expression in mouse suprarenal abdominal aortas. n = 6 per group. (G) MASMCs were isolated from the whole aortas of mice. q-PCR analysis of the mRNA levels of Hint1 in isolated MASMCs, HASMCs, and RASMCs stimulated with PBS or Ang II (10–6 M) (n = 6 per group). (H) MASMCs were isolated from the whole aortas of mice. Western blotting analysis of HINT1 in MASMCs, HASMCs, and RASMCs stimulated with PBS or Ang II (10–6 M) (n = 6 per group). Statistical analysis was performed by Student’s t test (B, C, and E–H). For all statistical plots, the data are presented as mean ± SEM.