Mangiferin activates Nrf2 to attenuate cardiac fibrosis via redistributing glutaminolysis-derived glutamate.

Abstract

Cardiac injury is followed by fibrosis, characterized by myofibroblast activation. Excessive deposition of extracellular matrix (ECM) impairs the plasticity of myocardium and results in myocardial systolic and diastolic dysfunction. Mangiferin is a xanthonoid derivative rich in plants mangoes and iris unguicularis, exhibiting the ability to ameliorate metabolic disorders. This study aims to investigate whether mangiferin attenuates cardiac fibrosis via redox regulation. The transverse aortic constriction (TAC) in mice induced cardiac fibrosis with impaired heart function. Oral administration of mangiferin (50 mg/kg, 4 weeks) inhibited myofibroblast activation with reduced formation of ECM. The impaired left ventricular contractive function was also improved by mangiferin. TGF-β1 stimulation increased glutaminolysis to fuel intracellular glutamate pool for the increased demands of nutrients to support cardiac myofibroblast activation. Mangiferin degraded Keap1 to promote Nrf2 protein accumulation by improving its stability, leading to Nrf2 activation. Nrf2 transcriptionally promotes the synthesis of antioxidant proteins. By activating Nrf2, mangiferin promoted the synthesis of glutathione (GSH) in cardiac fibroblasts, likely due to the consumption of glutaminolysis-derived glutamate as a source. Meanwhile, mangiferin promoted the exchange of intracellular glutamate for the import of extracellular cystine to support GSH generation. As a result of redistribution, the reduced glutamate availability failed to support myofibroblast activation. In support of this, the addition of extracellular glutamate or α-ketoglutarate diminished the inhibitory effects of mangiferin on cardiac myofibroblast proliferation and activation. Moreover, cardiac knockdown of Nrf2 attenuated the cardioprotective effects of mangiferin in mice subjected to TAC. In conclusion, we demonstrated that activated myofibroblasts were sensitive to glutamate availability. Mangiferin activated Nrf2 and redistributed intracellular glutamate for the synthesis of GSH, consequently impairing cardiac myofibroblast activation due to decreased glutamate availability. These results address that pharmacological activation of Nrf2 could restrain cardiac fibrosis via metabolic regulation.

• Authors: Junna Song, Yunxia Meng, Meng Wang, Lanzhu Li, Zhao Liu, Kaiyan Zheng, Lanfang Wu, Baolin Liu, Fangjie Hou, Aiying Li
• Journal: Pharmacological research (Pharmacol Res) Vol. 157 Pg. 104845 (07 2020) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 32353588 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Ltd. All rights reserved.

Chemical References

• NF-E2-Related Factor 2
• Nfe2l2 protein, mouse
• Nfe2l2 protein, rat
• Xanthones
• mangiferin
• Glutamic Acid
• Glutathione

Topics

• Animals
• Cardiomyopathies (genetics, metabolism, pathology, prevention & control)
• Disease Models, Animal
• Fibrosis
• Glutamic Acid (metabolism)
• Glutathione (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Myocardium (metabolism, pathology)
• Myofibroblasts (drug effects, metabolism, pathology)
• NF-E2-Related Factor 2 (agonists, genetics, metabolism)
• NIH 3T3 Cells
• Rats, Sprague-Dawley
• Signal Transduction
• Xanthones (pharmacology)