Extravascular administration of IGF1R antagonists protects against aortic aneurysm in rodent and porcine models
Authors/Creators
- 1. Capital Medical University
- 2. Seventh People's Hospital of Zhengzhou*
- 3. Nankai University
- 4. Harbin Medical University
- 5. Weihai Central Hospital*
Description
Aortic aneurysm is a life-threatening cardiovascular disease with high mortality. Herein, we first identified that plasma IGF1 was an independent risk factor in patients with abdominal aortic aneurysm. The IGF1 receptor was also activated in aneurysmal aortas from humans and mice, and SMC- or fibroblast-specific knockout of IGF1R attenuated AAA formation in mouse models, indicating the potential of IGF1R as a therapeutic target. Systemic administration of IGF1C peptide exerted an evident inhibitory effect on AAA formation and progression via competitive inhibition of IGF1 binding to its receptor and modulation of downstream AKT/mTOR signaling. However, global inhibition of IGF1R signaling induces side effects, including abnormal glucose metabolism, muscular disorder, and pain hypersensitivity observed after systemic administration of IGF1C or the commercialized IGF1R antagonists. Accordingly, local administration of IGF1C was realized via ultrasound-guided percutaneous injection of an IGF1C-loaded hydrogel, and the therapeutic efficacy was confirmed in a pig AAA model, demonstrating its translational potential for AAA therapy.
Notes
Funding provided by: National Natural Science Foundation of China
Crossref Funder Registry ID: https://ror.org/01h0zpd94
Award Number: 81925021
Funding provided by: National Natural Science Foundation of China
Crossref Funder Registry ID: https://ror.org/01h0zpd94
Award Number: 82241206
Funding provided by: National Natural Science Foundation of China
Crossref Funder Registry ID: https://ror.org/01h0zpd94
Award Number: 82330066
Funding provided by: National Natural Science Foundation of China
Crossref Funder Registry ID: https://ror.org/01h0zpd94
Award Number: 82102223
Funding provided by: National Key Research and Development Program of China Stem Cell and Translational Research
Award Number: 2018YFE0200503
Funding provided by: National Natural Science Foundation of China
Crossref Funder Registry ID: https://ror.org/01h0zpd94
Award Number: 81921004
Funding provided by: National Natural Science Foundation of China
Crossref Funder Registry ID: https://ror.org/01h0zpd94
Award Number: 82270499
Methods
Aneurysmal aortas were harvested from different groups (Control, GelMa, and IGF1C/GelMa) and mRNA was isolated from four aortas per sample using Trizol. Then, samples were sequenced by BGI using the DNBSEQ platform. The average mapping ratio with reference genome is 93.56%, and the average mapping ratio with gene is 74.53%; 18819 genes were identified. The complete dataset has not been processed.