HINT1 aggravates aortic aneurysm by targeting ITGA6/FAK axis in vascular smooth muscle cells
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
- Aihua Gu (ORCID: https://orcid.org/0000-0001-7576-9998)
- Zhi‐Jian Han
- Xuehui Yang
- Chenghui Yan
- Yong Ji
- Qiang Da (ORCID: https://orcid.org/0000-0001-5574-9236)
- Feng Chen (ORCID: https://orcid.org/0000-0003-0949-3182)
- Liping Xie (ORCID: https://orcid.org/0000-0001-6440-0239)
- Xiaoqiang Li (ORCID: https://orcid.org/0000-0003-2463-8298)
- Yaling Han (ORCID: https://orcid.org/0000-0003-4569-6737)
- Yan Zhang (ORCID: https://orcid.org/0000-0002-7508-4160)
- Liansheng Wang (ORCID: https://orcid.org/0000-0001-8538-6560)
- Xiaolong Du (ORCID: https://orcid.org/0000-0002-3957-8403)
- Xiaoqian Wang (ORCID: https://orcid.org/0000-0002-3144-8903)
- Ke Yan (ORCID: https://orcid.org/0000-0001-6314-0762)
- Shanshan Luo (ORCID: https://orcid.org/0000-0002-0961-4215)
- Bo Yu (ORCID: https://orcid.org/0000-0002-7257-2855)
- Wencheng Wu
- Zhi‐Ren Zhang (ORCID: https://orcid.org/0000-0003-1324-6934)
- Lulu Hu (ORCID: https://orcid.org/0000-0002-2008-3996)
- Yi Han (ORCID: https://orcid.org/0000-0003-2926-2007)
- Shan-zhen Sun (ORCID: https://orcid.org/0000-0003-2264-4141)
Institutions
- Harbin Medical University (CN)
- Nanjing Drum Tower Hospital (CN)
- Second Affiliated Hospital of Harbin Medical University (CN)
- Jiangsu Province Hospital (CN)
- Nanjing Medical University (CN)
- Nanjing University (CN)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-04-08
- DOI
- https://doi.org/10.1172/jci186628
- Citations
- 7
- Primary Topic
- Aortic aneurysm repair treatments
- Type
- article
- Field-Weighted Citation Impact
- 10.63
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Jiangsu Province