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HINT1 aggravates aortic aneurysm by targeting ITGA6/FAK axis in vascular smooth muscle cells
Yan Zhang, … , Liping Xie, Yong Ji
Yan Zhang, … , Liping Xie, Yong Ji
Published April 8, 2025
Citation Information: J Clin Invest. 2025;135(11):e186628. https://doi.org/10.1172/JCI186628.
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Research Article Cardiology Vascular biology

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

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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 4

Knockdown of Itga6 in VSMCs mitigates aortic aneurysm.

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Knockdown of Itga6 in VSMCs mitigates aortic aneurysm.
(A and B) Western...
(A and B) Western blotting (A) and q-PCR (B) analysis of ITGA6 in aorta samples from aortic aneurysm patients and normal aorta samples from donors (n = 6 per group). Six-week-old male Apoe–/–/Tagln-cre mice were injected with lentivirus vector encoding negative shRNA control (Lenti-shNC) or lentivirus vector encoding shRNA targeting Itga6 (Lenti-shItga6) with reverse loxP sites, which can be recognized by Cre recombinase. After injection for 14 days, mice were infused with saline or Ang II (1,000 ng/kg/min) for 28 days. (C) Representative photograph of aortas from saline or Ang II–infused Apoe–/–/Tagln-cre mice infected with Lenti-shNC or Lenti-shItga6. Scale bar: 2 mm. (D) Incidence of Ang II–induced aortic aneurysm. (E) Maximal abdominal lumen diameter in mice infused with saline (n = 6) or Ang II (n = 8–10), as measured by ultrasound. (F) Histopathological images of suprarenal abdominal aortas of saline- or Ang II–infused Apoe–/–/Tagln-cre mice infected with Lenti-shNC or Lenti-shItga6. Scale bars: 50 μm and 400 μm (insets). EVG, elastic van Gieson staining. (G) Representative in situ zymography photomicrographs showing MMP activity of suprarenal abdominal aortas. Scale bars: 20 μm. L, lumen. (H) Representative immunofluorescence staining of α-SMA expression in suprarenal abdominal aortas. Scale bars: 20 μm. L, lumen. (I) Western blotting analysis of the VSMC contractile markers (α-SMA and SM22) and synthetic marker (Vimentin) in suprarenal abdominal aortas from saline- or Ang II–infused Apoe–/–/Tagln-cre mice infected with Lenti-shNC or Lenti-shItga6 (n = 6 per group). Statistical analysis was performed by Student’s t test (A and B), Fisher’s exact test (D), or 1-way ANOVA (E and I). For all statistical plots, the data are presented as mean ± SEM.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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