Abstract
Background
The main path of sepsis-induced cardiomyopathy is the loss of endothelial barrier function. Neuregulin-1 (NRG-1) has beneficial effects on endothelial function.
Purpose
To investigate the effect of NRG-1 treatment on the protection of cardiac endothelial cells and the changes of RhoA/ROCK signaling in sepsis.
Methods
Rats were randomly divided into three groups: sham, LPS, and NRG-1. After successful induction of sepsis by lipopolysaccharide (LPS, 10mg/kg), rats were administered either a vehicle or recombinant human neuregulin-1 (rhNRG-1, 10μg/kg/d) for one or two days. We recorded their survival rate at 48h after sepsis. Hemodynamic methods were performed to assess cardiac function. We used immunofluorescence assay to detect von Willebrand Factor (vWF). Intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial growth factor (VEGF)levels in serum were measured by enzyme-linked immunosorbent assay (ELISA), and serum nitric oxide (NO) was detected by reductase method. We used transmission electron microscopy to observe changes in myocardial ultrastructure and western blot to assess expression of RhoA and ROCK1 protein.
Results
Sepsis impaired endothelial function manifested by increased ICAM-1, NO and VEGF levels in serum, NRG-1 treatment could significantly alleviate these increase (P<0.05). Compared with the vehicle, NRG-1 significantly decreased cardiac vascular permeability through increasing the expression of vWF on endothelial lining (P<0.05). Moreover, NRG-1 alleviated damages of ultrastructure of myocardial cells and suppressed the expression of RhoA and ROCK1 protein (P<0.05). Ultimately, NRG-1 improved the survival,and prevented hemodynamic derangement.
Levels of endothelial biomarker in serum ICAM-1 (pg/ml) VEGF (pg/ml) NO (pg/ml) Sham 24h 1564.74±94.41 0.84±0.28 203.27±1.81 Sham 48h 322.92±7.92 1.78±0.61 6.57±0.38 LPS 24h 5139.85±284.15† 3.11±0.04† 679.05±78.59† LPS 48h 950.41±25.23†‡ 4.65±0.30† 180.40±30.08†‡ NRG 24h 2772.18±164.45§ 0.30±0.04§ 355.14±23.41§ NRG 48h 578.57±28.97§‡ 1.02±0.45§ 104.67±2.13§‡ †p<0.05 vs. the sham group, §p<0.05 vs. the LPS group and ‡p<0.05 vs. the 24h group.
Effect of NRG-1 on endothelial cells
Conclusions
NRG-1 could alleviate endothelial injury in sepsis by strengthening the barrier function of vascular, reducing the secretion of endothelial-related biomarkers and inhibiting oxidative stress, thus improving cardiac function and survival rate, these effects may base on RhoA/ROCK signaling pathway. These may contribute to reverse the impaired endothelial cells in sepsis in the future.
Acknowledgement/Funding
The national natural science foundation of China (81772044)