Wei Haijun, Liu Runyu, Zhao Ming, Ma Yarong, He Yanzheng, Sun Xiaolei
Department of General Surgery (Vascular Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
Department of Vascular Surgery, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610000, China.
Biochem Biophys Rep. 2023 Oct 31;36:101567. doi: 10.1016/j.bbrep.2023.101567. eCollection 2023 Dec.
Ischemia‒reperfusion (IR) is a pathological process that causes secondary damage to blood vessels. However, whether IR can further worsen neointima formation after balloon injury and the detailed mechanism are unclear.
An model of balloon injury to the rat carotid artery was established to study the effect of IR following balloon injury on neointima formation. Smooth muscle cells (SMCs) were isolated from rat aortas and exposed to hypoxia-reoxygenation to mimic the IR process . The cell model was used to investigate the mechanism of IR-mediated neointima formation after balloon injury, which was further confirmed in an rat model.
IR aggravated neointima formation in the rat carotid artery 2 weeks after balloon injury compared with that observed in the absence of balloon injury ( < 0.001). Compared with that of normal SMCs in the rat carotid artery, the expression of IL-1β, a key proinflammatory cytokine associated with pyroptosis, was increased more than 3-fold in the IR-induced neointima ( < 0.0001) and contributed to the proliferation and migration of rat primary aortic SMCs ( < 0.0001). This process was alleviated by the antioxidant acetylcysteine (NAC), suggesting its partial dependence on intracellular ROS. In the rat model of IR following balloon injury in the carotid artery, the carotid artery that was locally transfected with AAV carrying sh-IL-1β or sh-caspase-1, which alleviated neointima formation, as indicated by a reduction in intima-media thickness in the rat carotid artery ( < 0.0001).
Our results suggested that IR could promote IL-1β production in SMCs in the carotid artery after balloon injury and aggravate neointimal hyperplasia, which was alleviated by silencing caspase-1/IL-1β signaling in SMCs in the carotid artery. These results suggest that IL-1β may be an effective target to combat IR-related neointima formation.
缺血再灌注（IR）是一种导致血管继发性损伤的病理过程。然而，IR是否会在球囊损伤后进一步加重新生内膜形成及其详细机制尚不清楚。
建立大鼠颈动脉球囊损伤模型，以研究球囊损伤后IR对新生内膜形成的影响。从大鼠主动脉分离平滑肌细胞（SMCs），并使其暴露于缺氧复氧环境以模拟IR过程。该细胞模型用于研究球囊损伤后IR介导新生内膜形成的机制，并在大鼠模型中进一步得到证实。
与未进行球囊损伤的情况相比，IR加重了球囊损伤后2周大鼠颈动脉的新生内膜形成（P<0.001）。与大鼠颈动脉正常SMCs相比，与焦亡相关的关键促炎细胞因子IL-1β在IR诱导的新生内膜中的表达增加了3倍以上（P<0.0001），并促进了大鼠原代主动脉SMCs的增殖和迁移（P<0.0001）。抗氧化剂乙酰半胱氨酸（NAC）缓解了这一过程，表明其部分依赖于细胞内活性氧。在颈动脉球囊损伤后IR的大鼠模型中，局部转染携带sh-IL-1β或sh-caspase-1的腺相关病毒（AAV）的颈动脉减轻了新生内膜形成，这通过大鼠颈动脉内膜中层厚度的减少得以表明（P<0.0001）。
我们的结果表明，IR可促进球囊损伤后颈动脉SMCs中IL-1β的产生并加重内膜增生，而颈动脉SMCs中caspase-1/IL-1β信号的沉默可缓解这种情况。这些结果表明，IL-1β可能是对抗IR相关新生内膜形成的有效靶点。
