Ischemia‒Reperfusion accelerates neointimal hyperplasia via IL-1β-mediated pyroptosis after balloon injury in the rat carotid artery

Haijun Wei; Runyu Liu; Ming Zhao; Yarong Ma; Yanzheng He; Xiaolei Sun

doi:10.1016/j.bbrep.2023.101567

Ischemia‒Reperfusion accelerates neointimal hyperplasia via IL-1β-mediated pyroptosis after balloon injury in the rat carotid artery

Biochem Biophys Rep. 2023 Oct 31:36:101567. doi: 10.1016/j.bbrep.2023.101567. eCollection 2023 Dec.

Authors

Haijun Wei^{1

2}, Runyu Liu^{1

3}, Ming Zhao⁴, Yarong Ma⁵, Yanzheng He¹, Xiaolei Sun^{1

6

7

8

9}

Affiliations

¹ Department of General Surgery (Vascular Surgery), The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
² Department of Vascular Surgery, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, 610000, China.
³ Department of Hepatobiliary Pancreatic Vascular Surgery, The Second Affiliated Hospital of Chengdu Medical College (China National Nuclear Corporation 416 Hospital), Chengdu, 610057, China.
⁴ Department of Gastroenterology, Clinical Medical College and the First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, 610500, China.
⁵ Department of Ophthalmology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
⁶ Department of Interventional Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.
⁷ Laboratory of Nucleic Acids in Medicine for National High-level Talents, Nucleic Acid Medicine of Luzhou Key Laboratory, Southwest Medical University, Luzhou, 646000, China.
⁸ Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, China.
⁹ Cardiovascular and Metabolic Diseases Key Laboratory of Sichuan, Luzhou, 646000, China.

Abstract

Background: 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.

Methods: An in vivo 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 in vitro. The in vitro cell model was used to investigate the mechanism of IR-mediated neointima formation after balloon injury, which was further confirmed in an in vivo rat model.

Results: IR aggravated neointima formation in the rat carotid artery 2 weeks after balloon injury compared with that observed in the absence of balloon injury (P < 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 (P < 0.0001) and contributed to the proliferation and migration of rat primary aortic SMCs (P < 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 (P < 0.0001).

Conclusion: 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.

Keywords: IL-1β; Neointimal hyperplasia; Pyroptosis; ischemia‒reperfusion.