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Ginsenoside Rb1 ameliorates endothelial dysfunction in sepsis: Targeting the RhoA/ROCK pathway to modulate
Shixi Shang1, Jingju Wang1, Ying Huang1
1Beijing Key Laboratory of TCM Basic Research on Prevention and Treatment of Major Disease, Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, 100070, China.
Background:
Sepsis-induced endothelial dysfunction drives organ injury through microcirculatory failure, characterized by barrier disruption and heterogeneous blood flow. Ginsenoside Rb1 (G-Rb1), a bioactive ginseng constituent, exhibits potent anti-inflammatory and antioxidant properties. This study investigates whether G-Rb1 ameliorates sepsis by preserving endothelial barrier integrity via modulating mitochondrial homeostasis and inhibiting the RhoA/ROCK pathway.
Methods:
A murine cecal ligation and puncture (CLP) sepsis model and lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs) were employed. Endothelial barrier function, mitochondrial dynamics, and inflammatory responses were assessed via histology, flow cytometry, Western blot, and Seahorse XF analysis. RhoA/ROCK inhibitor (Fasudil) and Drp1 inhibitor (Mdivi-1) served as mechanistic controls.
Results:
G-Rb1 significantly improved survival in CLP mice and attenuated lung injury. It suppressed pro-inflammatory cytokines (TNF-α, IL-6, IL-1β) in bronchoalveolar lavage fluid and rebalanced T cell percentage. In HUVECs, G-Rb1 restored endothelial junction proteins (VE-cadherin, ZO-1, Claudin-5), reduced ROS/MDA, and enhanced SOD/GSH/ATP levels. Mechanistically, G-Rb1 inhibited RhoA activation and ROCK-mediated Drp1 phosphorylation (Ser616), normalizing mitochondrial fission, membrane potential, and oxidative phosphorylation.
Conclusion:
G-Rb1 alleviates sepsis-induced endothelial dysfunction by suppressing the RhoA/ROCK/Drp1 axis, thereby restoring mitochondrial homeostasis and barrier integrity. These findings highlight G-Rb1 as a promising therapeutic candidate for sepsis management via dual modulation of cytoskeletal dynamics and mitochondrial quality control.
