Novel function of Roxadustat (FG-4592) as an anti-shock drug in sepsis by regulating mitochondrial oxidative stress and energy metabolism.

Abstract

BACKGROUND:

Septic shock is a serious clinical syndrome leading to high mortality. A new anti-anemia drug Roxadustat (FG-4592) protected against cardiac injury and hypertension. However, its effect and mechanism on shock and cardiac dysfunction induced by sepsis require to be investigated.

METHODS:

C57BL/6j mice received FG-4592 (10 mg/kg/day) by i.p injection, followed by lipopolysaccharide (LPS) or cecal ligation and puncture (CLP) treatment. Mortality and shock status were monitored during the experiment. Cardiac function was assessed using echocardiography and serum lactate dehydrogenase (LDH) and creatine kinase-MB (CK-MB) assay. TEM, COX-SDH staining and ATP production were used to evaluate mitochondrial function. A non-targeted metabolomic analysis was performed to evaluate the metabolic disorders.

RESULTS:

Both pre- and post-treatment of FG-4592 could improve the survival rate in LPS- and CLP-induced sepsis mice with a better effect in pre-treated animals. Meanwhile, FG-4592 improved systolic blood pressure and body temperature drop in septic mice along with alleviated cardiac dysfunction (as shown by the restoration of decreased LVEF and LVFS and increased LDH and CK-MB) and inflammation. Interestingly, we observed that FG-4592 improved mitochondrial oxidative stress possibly by upregulating the anti-oxidative enzymes of SOD2 and HO-1. Furthermore, FG-4592 improved the energy supply and glycerophospholipid metabolism in cardiomyocytes, possibly through upregulating the HIF-1α-targeted genes of LDHA and PDK1 in glycolysis and CHK-α, respectively.

CONCLUSIONS:

FG-4592 protected against mortality and shock in septic animals possibly by antagonizing mitochondrial oxidative stress and metabolic disorders.

GENERAL SIGNIFICANCE:

This study provides a potential of FG-4592 as a novel drug for treating septic shock.

• Authors: Guangfeng Long, Zhiyin Pei, Meng Wu, Ke Wei, Yang Du, Qian Wang, Yue Zhang, Songming Huang, Hongbing Chen, Weiwei Xia, Zhanjun Jia
• Journal: Biochimica et biophysica acta. General subjects (Biochim Biophys Acta Gen Subj) Vol. 1867 Issue 1 Pg. 130264 (01 2023) ISSN: 1872-8006 [Electronic] Netherlands
• PMID: 36273674 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 Elsevier B.V. All rights reserved.

Chemical References

• roxadustat
• Lipopolysaccharides

Topics

• Mice
• Animals
• Shock, Septic (drug therapy)
• Mice, Inbred C57BL
• Lipopolysaccharides (pharmacology)
• Sepsis (drug therapy, genetics)
• Energy Metabolism
• Oxidative Stress
• Heart Diseases