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Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice
Published on: September 28, 2015
HMGB2 Deficiency Mitigates Abdominal Aortic Aneurysm by Suppressing Ang-II-Caused Ferroptosis and Inflammation via
Hao Wu1, Legao Chen1, Kaiping Lu1
1Department of Vascular Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, 158 Shangtang Road, Hangzhou, Zhejiang, China.
Background:
Ferroptosis is a new form of cell death, which is closely related to the occurrence of many diseases. Our work focused on the mechanism by which HMGB2 regulate ferroptosis and inflammation in abdominal aortic aneurysm (AAA).
Methods:
Reverse transcription-quantitative polymerase chain reaction and western blot were utilized to assess HMGB2 levels. CCK-8 and flow cytometry assays were utilized to measure cell viability and apoptosis. We detected reactive oxygen species generation, Fe2+ level, and ferroptosis-related protein levels in Ang-II-treated VSMCs, which were typical characteristics of ferroptosis. Finally, the mice model of AAA was established to verify the function of HMGB2 in vivo.
Results:
Increased HMGB2 level was observed in Ang-II-treated VSMCs and Ang-II-induced mice model. HMGB2 depletion accelerated viability and impeded apoptosis in Ang-II-irritatived VSMCs. Moreover, HMGB2 deficiency neutralized the increase of ROS in VSMCs caused by Ang-II. HMGB2 silencing considerably weakened Ang-II-caused VSMC ferroptosis, as revealed by the decrease of Fe2+ level and ACSL4 and COX2 levels and the increase in GPX4 and FTH1 levels. Furthermore, the mitigation effects of shHMGB2 on Ang-II-induced VSMC damage could be counteracted by erastin, a ferroptosis agonist. Mechanically, HMGB2 depletion inactivated the NF-κβ signaling in Ang-II-treated VSMCs.
Conclusions:
Our work demonstrated that inhibition of HMGB2-regulated ferroptosis and inflammation to protect against AAA via NF-κβ signaling, suggesting that HMGB2 may be a potent therapeutic agent for AAA.
Insights
High mobility group box 2 (HMGB2) regulates ferroptosis and inflammation in abdominal aortic aneurysm (AAA). Inhibiting HMGB2 protects against AAA by modulating ferroptosis and inflammation via NF-κβ signaling.
Area of Science:
- Biomedical research
- Cellular biology
- Pathology
Background:
- Ferroptosis, a novel form of cell death, is implicated in various diseases.
- Abdominal aortic aneurysm (AAA) pathogenesis involves complex cellular mechanisms.
- This study investigates the role of High-mobility group box 2 (HMGB2) in regulating ferroptosis and inflammation within AAA.
Purpose of the Study:
- To elucidate the mechanism by which HMGB2 influences ferroptosis and inflammation in AAA.
- To determine the therapeutic potential of targeting HMGB2 in AAA treatment.
Main Methods:
- Quantitative polymerase chain reaction and western blotting were used to measure HMGB2 expression.
- Cell viability, apoptosis, reactive oxygen species (ROS) generation, and Fe2+ levels were assessed.
- Ferroptosis markers (ACSL4, COX2, GPX4, FTH1) and NF-κβ signaling pathway activation were analyzed.
- An in vivo mouse model of AAA was utilized to validate findings.
Main Results:
- HMGB2 levels were elevated in Angiotensin II (Ang-II)-treated VSMCs and in an AAA mouse model.
- HMGB2 depletion enhanced VSMC viability and reduced apoptosis.
- Silencing HMGB2 decreased ROS production and attenuated Ang-II-induced VSMC ferroptosis.
- HMGB2 inhibition reduced Fe2+ levels and altered ferroptosis-related protein expression (decreased ACSL4/COX2, increased GPX4/FTH1).
- HMGB2 depletion inactivated the NF-κβ signaling pathway in VSMCs.
Conclusions:
- HMGB2 inhibition mitigates ferroptosis and inflammation, offering protection against AAA.
- The protective effects are mediated through the NF-κβ signaling pathway.
- HMGB2 represents a potential therapeutic target for managing AAA.
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