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

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.

Proactive anti-inflammatory therapy with colchicine in the treatment of advanced stages of new coronavirus infection. The first results of the COLORIT study

“…Противовоспалительные эффекты колхицина связаны с несколькими механизмами, главное, с ингбированием инфламмасом [11]. При блокаде инфламмасом и уменьшении активности каспазного механизма снижается пироптоз (программируемая гибель клеток) и выработка цитокинов ИЛ-1β и ИЛ-18 [12]. В результате при различных триггерах (атеросклероз, гиперурикемия, вирусная инфекция) колхицин обладает противовоспалительным потенциалом и способен к предотвращению так называемого цитокинового шторма [13][14][15].…”

The Endothelium as a Target for Anti-Atherogenic Therapy: A Focus on the Epigenetic Enzymes EZH2 and SIRT1

“…In the context of atherogenesis, the endothelial cell-specific overexpression of SIRT1 blunts atherogenesis in hypercholesteraemic ApoE −/− mice [ 128 ]. SIRT1 decreases the endothelial reactivity to oxLDL [ 122 , 124 , 125 ], potentially by limiting its cellular uptake [ 121 ]. Furthermore, SIRT1 increases the endothelial production of NO by increasing the expression and the activity of the NO producing enzyme eNOS [ 122 , 127 , 162 ].…”

“…SIRT1 reduces p66shc expression by the deacetylation of histone 3 in its promoter region [ 112 ], resulting in the suppression of Nox-dependent [ 122 , 125 ] and mitochondrial [ 124 ] superoxide production. Third, SIRT1 reduces the formation of NLRP3 inflammasomes and the concurrent secretion of pro-inflammatory cytokines through a non-elucidated mechanism [ 121 ]. Fourth, SIRT1 precludes oxidative DNA damage and the concurrent induction of endothelial cell senescence [ 133 ], through a mechanism that involves the deacetylation of the p53 transcription factor [ 134 ].…”

“…For instance, inhibition of EZH2 as a result of GAS5 knockdown, a lncRNA that directly interacts with EZH2, promotes ABCA1-dependent hepatic LDL-C clearance [ 166 ]. Also, EZH2 inhibition mitigates foam cell oxLDL uptake in ApoE −/− mice [ 121 ]. Similarly, SIRT1 activation limits hepatic LDL-C production [ 161 ] and reduces foam cell formation [ 167 ] in atherosclerotic mice.…”

Is it time to introduce anti-inflammatory drugs into secondary cardiovascular prevention: evidence from clinical trials?

“…Colchicine is a plant-derived alkaloid that reduces the synthesis of IL-1β, IL-2 and IL-6 by inhibiting tubulin polymerization and consequently the nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) family pyrin domain containing protein 3 (NLRP3) inflammasome arrangement in monocytes and other cells [21,22] . Colchicine is also reported to downregulate neutrophil adhesion and recruitment, superoxide anion production and mast cell degranulation [21,22] and to inhibit cholesterol-crystal induced endothelial pyroptosis, oxidative stress and monocyte chemotaxis [23] , as well as platelet aggregation and endothelial cell prothrombotic effects induced by oxidized LDL [24,25] . In an animal model, colchicine protected against acute cerebral ischemia by inhibiting exocytosis and chemotaxis [26] .…”