Mitogen-activated Protein Kinase big Mitogen-activated Kinase-1 Mediates Protection in Liver Ischemia/Reperfusion...

Hepatic ischemia/reperfusion injury (IRI) is a major complication occurring in hemorrhagic shock, liver resection, and transplantation. Big mitogen-activated kinase-1 (BMK1), a member of the mitogen-activated protein kinases family, is essential for regulating endothelial cell integrity and organ development.

We explored the putative role of BMK1 in human liver transplant recipients and in a murine model of partial warm liver IRI.

Liver biopsies from adult transplant patients (n = 60) revealed that increased intrahepatic BMK1 expression was associated with well-preserved histology and improved graft function. In mice, the ischemia insult (90 min) induced hepatocellular BMK1 expression, peaking at 6 h of reperfusion. Inhibiting intrahepatic BMK1 (siRNA/chemically) made livers more vulnerable to IR stress, as evidenced by elevated serum alanine aminotransferase levels, damaged hepatic architecture, increased necrosis, and inflammation. Conversely, BMK1-overexpression protected livers from IR stress in a Krüppel-like factor 4 (KLF4)-dependent manner. Further in vivo and in vitro experiments confirmed that BMK1 overexpression upregulated hepatic yes-associated protein (YAP) mRNA/protein levels and promoted YAP dephosphorylation, whereas YAP silencing abrogated the protective effects of BMK1. The hypoxia-reoxygenation in vitro assay indicated that hepatocellular BMK1 regulated YAP function via itchy E3 ubiquitin protein ligase-related ubiquitination to large tumor suppressor homolog 1. Hypoxia-reoxygenation stress in BMK1-overexpressed hepatocytes resulted in increased intracellular itchy E3 ubiquitin protein ligase and decreased phosphorylated large tumor suppressor homolog 1, whereas no change in the phosphorylation level of mammalian sterile 20-like protein kinase-1. Furthermore, dual hepatocyte immunofluorescence staining revealed that BMK1 relied on the nuclear YAP-KLF4 cooperation, as hepatic deficiency of either BMK1, YAP, or KLF4 enhanced the severity of hepatic IRI.

This study documents the crucial role/underlying mechanism of BMK1 signaling and points to a novel target to minimize hepatocellular dysfunction in IR-stressed liver transplantation.