Protection of cultured human hepatocytes from hydrogen peroxide-induced apoptosis by relaxin-3

Abstract

Previous studies have suggested that hepatocyte apoptosis may be a fundamental underlying mechanism of liver injury and diseases, such as liver fibrosis. Relaxin‑3 has been reported to have anti‑fibrotic actions in the heart and to attenuate isoproterenol‑induced myocardial injury; however, the beneficial role of relaxin‑3 on hepatocyte apoptosis remains to be elucidated. The aim of the present study was to explore the role and possible mechanisms of relaxin‑3 through hydrogen peroxide (H2O2)‑induced apoptosis in primary human hepatocytes. Cells were treated with relaxin‑3 and then cell viability, morphological features, the presence of cleaved caspases as well as the levels of endoplasmic reticulum stress (ERS) protein markers and autophagy markers were evaluated. The H2O2 group showed significantly decreased cell viability, increased apoptosis as well as upregulation of caspases (cleaved caspase‑3, ‑8 and ‑9) and ERS protein markers compared with those of the control group. However, cells treated with relaxin‑3 (10 ng/ml) demonstrated improved cell viability, reduced apoptosis and decreased expression of cleaved caspases and ERS markers. However, the expression of autophagy markers remained unchanged following H2O2‑induced apoptosis and relaxin‑3 treatment. In conclusion, relaxin‑3 was shown to protect hepatocytes from H2O2‑induced apoptosis via downregulation of cleaved caspase‑8 and ‑9, as well as inhibition of the ERS pathway.

Disulfide-HMGB1 signals through TLR4 and TLR9 to induce inflammatory macrophages capable of innate-adaptive crosstalk in human liver transplantation

“…Oxidative stress from ROS production also contributes to graft injury because it is detrimental to liver parenchymal cell survival. 24 , 32 , 33 These results expand on previous findings of M1 macrophages initiating and sustaining IRI pathology. 18 , 34 …”

Increased plasma levels of relaxin-2 in liver cirrhotic patients

“…Some studies suggested that relaxin-3 was involved in modulating brain function in combination with RXFP3 [15], and one study showed that relaxin-3 exerts its effects by binding to RXFP1 (the primary relaxin-2 receptor) [16]. Our previous studies demonstrated that relaxin-3 may attenuate hepatocyte apoptosis and protect against liver injury by inhibiting endoplasmic reticulum stress [13]. We found that plasma relaxin-3 levels were not significantly different between patients with liver cirrhosis and control subjects, however, plasma relaxin-2 concentrations were significantly positively correlated with relaxin-3 concentrations in patients with liver cirrhosis.…”

“…A single adenoviral delivery of relaxin-2 in the liver attenuated established hepatic fibrosis by suppressing collagen crosslinking and enhancing collagen degradation [12]. Our previous study showed that relaxin-3, the 'ancestral' member of the relaxin peptide family, inhibits ROS-induced hepatic cell apoptosis [13].…”

Overexpression of C‑sis inhibits H2O2‑induced Buffalo rat liver cell apoptosis in�vitro and alleviates liver injury in a rat model of fulminant hepatic failure

“…H 2 O 2 is a potent oxidant, and studies have shown that H 2 O 2 can induce hepatocyte apoptosis ( 48 , 49 ). In the present study, LPS and D-GalN did not exert a significant effect on the proliferation of the BRL liver cell line (data not shown).…”