Sirt1 Protects Endothelial Cells against LPS-Induced Barrier Dysfunction

Area of Science:

• Vascular biology
• Cellular signaling
• Immunology

Background:

• Sepsis is a life-threatening condition characterized by widespread inflammation and microvascular dysfunction.
• Endothelial barrier integrity is crucial for maintaining vascular homeostasis, and its disruption is a hallmark of sepsis.

Purpose of the Study:

• To investigate the role of Sirtuin 1 (Sirt1) in lipopolysaccharide (LPS)-induced endothelial hyperpermeability.
• To explore the involvement of the receptor for advanced glycation end products (RAGE) pathway in Sirt1 regulation during sepsis.

Main Methods:

• Utilized cell culture models (pulmonary microvascular vein endothelial cells, human umbilical vein endothelial cells) and animal models (wild-type and RAGE-knockout mice).
• Employed pharmacological inhibitors (ex527, SRT1720), small interfering RNA (siRNA), antibodies, and dextran leakage assays.
• Assessed protein expression, activity, ubiquitination, and reactive oxygen species levels.

Main Results:

• LPS exposure downregulated Sirt1 and increased endothelial cell permeability.
• Sirt1 activation reversed LPS-induced hyperpermeability, VE-cadherin disruption, and oxidative stress.
• RAGE signaling contributed to LPS-induced Sirt1 downregulation.
• Sepsis-induced microvascular leakage was attenuated in Sirt1 and RAGE knockout models.
• Sirt1 activation preserved superoxide dismutase 2 activity and modulated NADPH oxidase 4 and p53/β-catenin pathways.

Conclusions:

• Sirt1 plays a protective role against LPS-induced endothelial hyperpermeability and microvascular dysfunction in sepsis.
• RAGE signaling is implicated in the regulation of Sirt1 during sepsis.
• Targeting Sirt1 represents a potential therapeutic strategy for sepsis-associated vascular complications.