Colchicine Alleviates Cholesterol Crystal-Induced Endothelial Cell Pyroptosis through Activating AMPK/SIRT1 Pathway.

Mengyue Yang,Bo Yu,Lu Zhang,Ruoxi Zhang,Jingbo Hou,Shenglong Hou,Baihe Han,Dandan Liu,Hang Lv,Xingtao Huang,Xuedong Wang,Qi Liu,Gang Wang

doi:10.1155/2020/9173530

Abstract

Cholesterol crystal- (CC-) induced endothelial cell inflammation and pyroptosis play an important role in the development of cardiovascular diseases, especially in atherosclerosis (AS). Increasing evidence suggests that cholesterol crystals are known to be a pivotal pathological marker of atherosclerotic plaque vulnerability. As a classical nonspecific anti-inflammatory drug, colchicine has been widely used in the treatment of acute gout. However, whether colchicine could alleviate CC-induced endothelial cell injury and the related mechanisms remains to be addressed. In this study, the protective effect of colchicine on human umbilical vein endothelial cells (HUVECs) was confirmed. Our results revealed that after cotreatment with colchicine and cholesterol crystals in endothelial cells, the uptake of cholesterol crystals was significantly decreased, the cell viability was obviously increased, and the release of lactate dehydrogenase (LDH) and the number of pyroptotic cells decreased significantly; then, the expression of NLRP3 inflammasome-related proteins and various inflammatory factors was also visibly suppressed; moreover, as a potent activator of NLRP3 inflammasome, the intracellular ROS level was clearly reduced, while mitochondrial membrane potential improved significantly. In addition, the expression levels of AMP-dependent kinase (AMPK) pathway-related proteins as well as various antioxidant enzymes were elevated notably in varying degrees. However, the above effects of colchicine were completely offset by the treatment of siRNA targeting AMPKα and Sirtuin1 (SIRT1). Therefore, we conclude that colchicine plays a crucial role in alleviating the intracellular inflammatory response and NLRP3 inflammation activation, attenuating the levels of cellular oxidative stress and pyroptosis in endothelial cells via regulating AMPK/SIRT1 signaling, which may be a concrete mechanism for the secondary prevention of cardiovascular diseases.

Highlights

Coronary heart disease (CHD) is the most fatal disease in the world, and acute coronary syndrome (ACS) remains a leading cause of morbidity and mortality
It can be activated by a variety of damaging molecules such as ATP, uric acid crystal, cholesterol crystal, and asbestos, triggering an intensively aseptic inflammatory response via Oxidative Medicine and Cellular Longevity upregulating the expression of multiple proinflammatory cytokines [4]; beyond that, pyroptosis implementing protein GSDMD is cleaved by activated caspase-1, inducing caspase1-dependent pyroptotic cell death [5]
We discovered that colchicine could upregulate the expression and activity of various antioxidant enzymes, inhibit reactive oxygen species (ROS) production and NLRP3 inflammasome activation, and antagonize endothelial cell pyroptosis which was induced by CC via activating the AMP-dependent kinase (AMPK)-SIRT1 pathway

Summary

Introduction

Coronary heart disease (CHD) is the most fatal disease in the world, and acute coronary syndrome (ACS) remains a leading cause of morbidity and mortality. Extensive studies have found that CC appeared in the initiation of atherosclerotic plaque and was associated with early inflammatory response [2]. NLRP3 inflammasome is a macromolecule-polyprotein complex that regulates the production of the IL-1 family and plays an important role in the pathogenesis of AS. It can be activated by a variety of damaging molecules such as ATP, uric acid crystal, cholesterol crystal, and asbestos, triggering an intensively aseptic inflammatory response via Oxidative Medicine and Cellular Longevity upregulating the expression of multiple proinflammatory cytokines [4]; beyond that, pyroptosis implementing protein GSDMD is cleaved by activated caspase-1, inducing caspase1-dependent pyroptotic cell death [5]. Studies have demonstrated that reactive oxygen species (ROS) plays a crucial role in the activation of inflammasome, and pretreatment with various ROS scavengers represses NLRP3 inflammasome activation in response to a series of agonists [6, 7]

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Discussion

Conclusion