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Front Biosci (Landmark Ed). 2020 Jan 1;25:283-298.

Simvastatin improves lysosome function via enhancing lysosome biogenesis in endothelial cells.

Author information

1
School of Pharmacy, Hubei University of Science and Technology, Xianning, China.
2
Department of Pharmacological & Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204.
3
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA, 23298.
4
Department of Pharmacological & Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, 33TUxli61@central.uh.eduU33T.

Abstract

Nlrp3 inflammasomes were shown to play a critical role in triggering obesity-associated early onsets of cardiovascular complications such as endothelial barrier dysfunction with endothelial hyperpermeability. Statins prevent endothelial dysfunction and decrease cardiovascular risk in patients with obesity and diabetes. However, it remains unclear whether statin treatment for obesity-induced endothelial barrier dysfunction is in part due to the blockade of Nlrp3 inflammasome signaling axis. The results showed that simvastatin, a clinically and widely used statin, prevented free fatty acid-induced endothelial hyperpermeability and disruption of ZO-1 and VE-cadherin junctions in mouse microvascular endothelial cells (MVECs). This protective effect of simvastatin was largely due to improved lysosome function that attenuated lysosome injury-mediated Nlrp3 inflammasome activation and subsequent release of high mobility group box protein-1 (HMGB1). Mechanistically, simvastatin induces autophagy that promotes removal of damaged lysosomes and also promotes lysosome regeneration that preserves lysosome function. Collectively, simvastatin treatment improves lysosome function via enhancing lysosome biogenesis and its autophagic turnover, which may be an important mechanism to suppress Nlrp3 inflammasome activation and prevents endothelial hyperpermeability in obesity.

PMID:
31585890

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