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Inhibition of glutaminolysis alleviates myocardial fibrosis induced by angiotensin II

WANG Pan-Pan^1,2, BAI Hao-Miao³, HE Si-Yu³, XIA Zi-Qi³, LIU Mei-Jie², AN Jiong², ZHOU Jia-Heng², LI Chen-Han^1,2, ZHANG Wei^1,2, ZHANG Xing², WANG Xin-Pei², LI Jia^2,*

¹College of Life Sciences, Northwest University, Xi’an 710069, China；²School of Aerospace Medicine, Air Force Medical University, Xi’an 710032, China；³Cadet Regiment, School of Basic Medical Sciences, Air Force Medical University, Xi’an 710032, China

Abstract

The present study was aimed to investigate the role and mechanism of glutaminolysis of cardiac fibroblasts (CFs) in hypertension-induced myocardial fibrosis. C57BL/6J mice were administered with a chronic infusion of angiotensin II (Ang II, 1.6 mg/kg per d) with a micro-osmotic pump to induce myocardial fibrosis. Masson staining was used to evaluate myocardial fibrosis. The mice were intraperitoneally injected with BPTES (12.5 mg/kg), a glutaminase 1 (GLS1)-specific inhibitor, to inhibit glutaminolysis simultaneously. Immunohistochemistry and Western blot were used to detect protein expression levels of GLS1, Collagen I and Collagen III in cardiac tissue. Neonatal Sprague-Dawley (SD) rat CFs were treated with 4 mmol/L glutamine (Gln) or BPTES (5 μmol/L) with or without Ang II (0.4 μmol/L) stimulation. The CFs were also treated with 2 mmol/L α-ketoglutarate (α-KG) under the stimulation of Ang II and BPTES. Wound healing test and CCK-8 were used to detect CFs migration and proliferation respectively. RT-qPCR and Western blot were used to detect mRNA and protein expression levels of GLS1, Collagen I and Collagen III. The results showed that blood pressure, heart weight and myocardial fibrosis were increased in Ang II-treated mice, and GLS1 expression in cardiac tissue was also significantly up-regulated. Gln significantly promoted the proliferation, migration, mRNA and protein expression of GLS1, Collagen I and Collagen III in the CFs with or without Ang II stimulation, whereas BPTES significantly decreased the above indices in the CFs. α-KG supplementation reversed the inhibitory effect of BPTES on the CFs under Ang II stimulation. Furthermore, in vivo intraperitoneal injection of BPTES alleviated cardiac fibrosis of Ang II-treated mice. In conclusion, glutaminolysis plays an important role in the process of cardiac fibrosis induced by Ang II. Targeted inhibition of glutaminolysis may be a new strategy for the treatment of myocardial fibrosis.

Key words: glutaminolysis; glutaminase 1; myocardial fibrosis

Received: 　　Accepted:

Corresponding author: 李嘉　　E-mail: jiali816@fmmu.edu.cn

DOI: 10.13294/j.aps.2023.0029

Citing This Article：

WANG Pan-Pan, BAI Hao-Miao, HE Si-Yu, XIA Zi-Qi, LIU Mei-Jie, AN Jiong, ZHOU Jia-Heng, LI Chen-Han, ZHANG Wei, ZHANG Xing, WANG Xin-Pei, LI Jia. Inhibition of glutaminolysis alleviates myocardial fibrosis induced by angiotensin II. Acta Physiol Sin 2023; 75 (2): 179-187 (in Chinese with English abstract).