1. Local upregulation of interleukin-1 beta in aortic dissecting aneurysm: correlation with matrix metalloproteinase-2, 9 expression and biomechanical decrease
Yun-Fei Jiang, Ling-Ling Guo, Li-Wei Zhang, Yong-Xin Chu, Guang-Lang Zhu, Ye Lu, Lei Zhang, Qing-Sheng Lu, Zai-Ping Jing Interact Cardiovasc Thorac Surg. 2019 Mar 1;28(3):344-352. doi: 10.1093/icvts/ivy256.
Objectives: Our goal was to examine whether interleukin-1 beta (IL-1β) originates locally and its possible relationship with matrix metalloproteinases (MMPs), apoptosis, elastin fibres and biomechanics in aortic dissecting aneurysms (DAs). Methods: Aortic DAs were induced in 24 rats with β-aminopropionitrile (BAPN); another 12 rats without BAPN were designated as controls. Then IL-1β levels were measured both in the circulation and in local aortic specimens. The expression of MMP-2 and MMP-9 and Victoria blue and TUNEL staining were also detected. Biomechanical parameters such as the elasticity modulus were used to detect the biomechanical changes in the aortic wall. The correlation of IL-1β, MMP-2, MMP-9, apoptosis and biomechanical properties was analysed. Results: Seventeen rats (17/24, 71%) in the BAPN-treated group died of DA rupture. IL-1β levels were dramatically increased in the DA specimens but not in the circulation. Victoria blue staining confirmed the formation of the DA and the reduction of elastin content after induction by BAPN. The extent of apoptosis in the aortic media was dramatically higher in rats with BAPN-induced DA than that in the control group and that in rats treated with BAPN but without DA. MMP-2 and MMP-9 levels were significantly increased in BAPN-treated rats compared to the controls, but no statistical significance was found between rats with and without DA. There were significant differences in biomechanical parameters, such as the elasticity modulus. Among the 3 groups, IL-1β was positively correlated with MMP-2 and MMP-9 levels and with the elasticity modulus but not with apoptosis. Conclusions: Local IL-1β might participate in the formation of aortic DA through the upregulation of MMP-2 and MMP-9 and the breakage of elastin fibres, which finally weakens the biomechanical properties of the aortic wall.
2. Blocking Interleukin-1 Beta Reduces the Evolution of Thoracic Aortic Dissection in a Rodent Model
Ling-Ling Guo, Meng-Tao Wu, Li-Wei Zhang, Yong-Xin Chu, Peng Tian, Zai-Ping Jing, Jia-Si Li, Yu-Dong Sun, Kak K Yeung, Lei Zhang Eur J Vasc Endovasc Surg. 2020 Dec;60(6):916-924. doi: 10.1016/j.ejvs.2020.08.032. Epub 2020 Sep 29.
Objective: Thoracic aortic dissection (TAD) is associated with matrix changes, biochemical changes, and inflammatory markers like interleukin-1 beta (IL-1β). However, the exact mechanism remains unknown. This study aimed to investigate the role of IL-1β, matrix metalloproteinase (MMP)-2, MMP-9, smooth muscle cell apoptosis, and elastic fibre fracture in the development of TAD in a rat model. Methods: The TAD rat model was induced by β-aminopropionitrile (BAPN). TAD was investigated in 112 male Sprague-Dawley rats, which were equally divided into four groups of 28 rats (Control, BAPN, BAPN + IL-1β, and BAPN + IL-1β antibody). Systolic blood pressure, survival, and the development of TAD were measured after six weeks. Expression of IL-1β, MMP-2, and MMP-9 was measured by Western blot. Apoptosis, aortic elastin concentration, and biomechanical characteristics were measured by the TdT mediated dUTP nick end labelling assay, Victoria blue staining, and in vitro testing. Results: During six weeks, the mortality was 0% (0/28) in the control group, 53.6% (15/28) in the BAPN group (p < .001 compared with the control group), 75.0% (21/28) in the BAPN + IL-1β group (p = .007 compared with the BAPN group), and 35.7% (10/28) in the BAPN + IL-1β antibody group (p = .023 compared with BAPN group and p < .001 compared with the BAPN + IL-1β group). IL-1β treatment deteriorates BAPN induced mortality and aneurysm expansion, which were attenuated by anti-IL-1β treatment. In BAPN + IL-1β group, stress and strain parameters were decreased by 13.5%-53.5% and elastin content was decreased by 14%, and IL-1β, MMP-2, and MMP-9 were expressed higher by 117%, 108%, and 75% when compared with the rats in the BAPN group. Contrarily, in the BAPN + IL-1β antibody group, the above changes could be completely (strain, elastin content, and expression of MMP-2) or partly (elasticity modulus, stress, and expression of MMP-9) blocked by anti-IL-1β treatment. Conclusion: IL-1β plays a critical role in TAD formation by altering the expression of MMP-2 and MMP-9, degrading the aortic wall matrix, causing elastic fibre rupture, and changing the stress or strain of the aortic wall. Anti-IL-1β reduces the later effects and could be one of the molecular targets for prognosis and drug treatment of TAD in the future.
3. Phenotypic switching of vascular smooth muscle cells in animal model of rat thoracic aortic aneurysm
Naihui Mao, Tianxiang Gu, Enyi Shi, Guangwei Zhang, Lei Yu, Chun Wang Interact Cardiovasc Thorac Surg. 2015 Jul;21(1):62-70. doi: 10.1093/icvts/ivv074. Epub 2015 Mar 31.
Objectives: To explore if there is phenotypic switching in the vascular smooth muscle cells (vSMCs) of rat thoracic aortic aneurysms and the role it plays in the process of aneurysm formation. Methods: Male SD white rats were assigned randomly to the aneurysm group (AG) and control group (CG). The animal aneurysm model was obtained by soaking the peri-adventitia with porcine pancreatic elastase (PPE). The rats in the CG were given saline to provide contrast. A vascular ultrasound was used to monitor the diameter of the aneurysm. Specimens were stained with haematoxylin and eosin (HE), and α-SMA, SM-MHC, matrix metalloproteinase (MMP)-2 and MMP-9 were detected with immunohistochemistry staining. α-SMA, SM-MHC, MMP-2 and MMP-9 were conducted with western blot. vSMCs taken from the descending aorta of both of the CG and AG were separated and cultured until Passage 3. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method were used to analyse cell proliferation. Western blot was used to evaluate MMP-2, MMP-9 expression and flow cytometry was employed to assess cell apoptosis. Results: Vascular ultrasound showed obvious dilatation of soaked descending aorta. HE staining showed thickening of thoracic aorta and disarrangement of cells after soaking with PPE. Immunohistochemistry staining showed high expression of MMP-2 and MMP-9 but low expression of SM-MHC and α-SMA in the AG. Tissue western blot analysis of the AG showed that the protein gray value was high in MMP-2 and MMP-9, but low in α-SMA and SM-MHC, which had statistical differences compared with CG with a P-value of <0.05. MTT analysis showed vSMC proliferation activity was higher in the AG than in the CG. Flow cytometry analysis revealed that cell apoptosis between the control and aneurysm groups had significant statistical differences. Conclusions: There is vSMC phenotypic switching in animal models as seen through the rat thoracic aortic aneurysms. This may play an important role in the formation of aneurysms. Our findings are relevant to human aneurysms and may be conducive in the research of aortic aneurysm pathology and treatment.
