Abstract
Background Serine hydroxymethyltransferase 2 (SHMT2) activity ensures that cells have a survival advantage in ischemic conditions and regulates redox homeostasis. In this study, we aimed to investigate the role of SHMT2 after hepatic ischemia-reperfusion (IR), which involves hypoxia, ischemic conditions, and cell apoptosis. Methods A 70% IR model was established in C57BL/6J mice with or without SHMT2 knockdown. H&E staining, liver weight/body weight, serum alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels and cell apoptosis were tested to analyze liver damage and function. Then, the related cellular signals were probed. Results The level of SHMT2 protein was significantly increased at 24 h and 48 h after IR (p < 0.001). Mice in the shSHMT2 group showed more necrotic areas and histological damage at 24 h (p < 0.01) after IR and higher levels of serum ALT and AST (p < 0.05) compared with those of mice in the scramble group. After IR for 24 h, the expression of TUNEL in the shSHMT2 group was significantly higher than that in the scramble group, as shown by histological analysis (p < 0.01). Mechanistically, the JNK/P53 signaling pathway was activated by IR, and knockdown of SHMT2 exacerbated hepatocyte apoptosis. Conclusions Knockdown of SHMT2 worsens IR injury through the ROS/JNK/P53 signaling pathway. Our discovery expands the understanding of both molecular and metabolic mechanisms involved in IR. SHMT2 is a possible therapeutic target to improve the prognosis of liver transplantation (LT) and subtotal hepatectomy.
Highlights
Hepatic ischemia-reperfusion (IR) injury may lead to liver graft nonfunction and liver failure following resection and liver transplantation [1]
The portal vein branch on the left side of the liver was clamped with a topless blood clip, resulting in 70% hepatic ischemia. e hemostatic clip was released to open the blood return after 60 minutes of clamping. e mice were divided stochastically into four groups: sham group, in which the mice only received the open laparotomy without ischemic treatment; negative control group, in which the mice were injected with saline through tail vein before undergoing the operation; AAV8-scramble group, in which the mice were injected via the tail vein with AAV8-scramble adeno-associated virus 4 weeks before undergoing the operation; and AAV8shSHMT2 group, in which the mice were injected via the tail vein with AAV8-ShRNA-Serine hydroxymethyltransferase 2 (SHMT2) adeno-associated virus 4 weeks before undergoing the operation
Serine hydroxymethyl transferase (SHMT) is a pyridoxal-5′phosphate-dependent enzyme functioning in the serine/ glycine synthesis pathway and single-carbon metabolism, which provides essential precursors for protein and nucleic acid synthesis for cancer growth and metastasis [16]
Summary
Hepatic ischemia-reperfusion (IR) injury may lead to liver graft nonfunction and liver failure following resection and liver transplantation [1]. SHMT2 plays a regulatory role in cell proliferation and redox homeostasis by regulating small molecular metabolites [4]. SHMT2 activity ensures that cells in ischemia conditions survive by limiting pyruvate kinase (PKM2) and reducing oxygen consumption [5]. SHMT2 has been verified as a necessity for maintaining redox homeostasis and cell survival under hypoxic conditions [6]. Serine hydroxymethyltransferase 2 (SHMT2) activity ensures that cells have a survival advantage in ischemic conditions and regulates redox homeostasis. We aimed to investigate the role of SHMT2 after hepatic ischemiareperfusion (IR), which involves hypoxia, ischemic conditions, and cell apoptosis. The JNK/P53 signaling pathway was activated by IR, and knockdown of SHMT2 exacerbated hepatocyte apoptosis. Knockdown of SHMT2 worsens IR injury through the ROS/JNK/P53 signaling pathway. SHMT2 is a possible therapeutic target to improve the prognosis of liver transplantation (LT) and subtotal hepatectomy
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