2. Academic Validation
  3. Chloroquine is a safe autophagy inhibitor for sustaining the expression of antioxidant enzymes in trophoblasts

Chloroquine is a safe autophagy inhibitor for sustaining the expression of antioxidant enzymes in trophoblasts

  • J Reprod Immunol. 2023 Feb:155:103766. doi: 10.1016/j.jri.2022.103766.
Atsushi Furuta 1,  Tomoko Shima 1,  Mihoko Yoshida-Kawaguchi 1,  Kiyotaka Yamada 1,  Ippei Yasuda 1,  Sayaka Tsuda 1,  Akemi Yamaki-Ushijima 1,  Satoshi Yoneda 1,  Kazuma Higashisaka 2,  Shi-Bin Cheng 3,  Kenji Matsumoto 4,  Yasuo Tsutsumi 5,  Surendra Sharma 3,  Shigeru Saito 6,  Akitoshi Nakashima 7
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Toyama Autophagy Team in Gynecology and Obstetrics, University of Toyama, 2630 Sugitani, Toyama 9300194, Japan.
  • 2 Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan.
  • 3 Departments of Pediatrics, Women and Infants Hospital of Rhode Island, Warren Alpert Medical School of Brown University, Providence, RI 02905, USA.
  • 4 Department of Allergy and Clinical Immunology, National Research Institute for Child Health and Development, Tokyo, Japan.
  • 5 Laboratory of Toxicology and Safety Science, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan; The Center for Advanced Medical Engineering and Informatics, Osaka University, 1-6, Yamadaoka, Suita, Osaka 565-0871, Japan.
  • 6 University of Toyama, 3190 Gofuku, Toyama 9308555, Japan.
  • 7 Department of Obstetrics and Gynecology, Toyama Autophagy Team in Gynecology and Obstetrics, University of Toyama, 2630 Sugitani, Toyama 9300194, Japan. Electronic address: [email protected].
PMID: 36470134 DOI: 10.1016/j.jri.2022.103766
Abstract

Inhibition of Autophagy contributes to the pathophysiology of preeclampsia. Although chloroquine (CHQ) is an Autophagy inhibitor, it can reduce the occurrence of preeclampsia in women with systemic lupus erythematosus. To clarify this important clinical question, this study aimed to address the safety of CHQ in trophoblast cells from the viewpoint of homeostasis, in which the anti-oxidative stress (OS) response and Autophagy are involved. We used Western blotting to evaluate the protein levels in the trophoblast cells. The expression levels of heme oxygenase-1 (HO-1), an anti-OS enzyme, mediate resistance to OS induced by hydrogen peroxide (H2O2) in trophoblast cell lines. Among the Autophagy modulators, bafilomycin A1 (BAF), an Autophagy inhibitor, but not Autophagy activators, suppressed HO-1 expression in BeWo cells; CHQ did not suppress HO-1 expression in BeWo cells. To clarify the role of Autophagy in HO-1 induction, we observed no difference in HO-1 induction by H2O2 between autophagy-normal and autophagy-deficient cells. As for the mechanism of HO-1 induction by OS, BAF suppressed HO-1 induction by downregulating the expression of neighbor of BRCA1 gene 1 (NBR1) in the selective p62-NBR1-nuclear factor erythroid 2-related factor 2 (Nrf2) Autophagy pathway. CHQ did not inhibit HO-1 expression by sustaining NBR1 expression in human villous tissues compared to BAF treatment. In conclusion, CHQ is a safer medicine than BAF for sustaining NBR1, which resist against OS in trophoblasts by connecting selective Autophagy and the anti-OS response.

Keywords

Autophagy; Chloroquine; HO-1; NBR1; Oxidative stress.

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