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HSPA8 Is Identified as a Novel Regulator of Hypertensive Disorders in Pregnancy by Modulating the β-Arrestin1/A1AR Axis

  • Maternal Fetal Medicine/Biology: Original Article
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Abstract

Heat shock protein alpha 8 (HSPA8) was found to be downregulated in the placentas of patients with hypertensive disorders in pregnancy (HDP). We aim to explore the underlying role and mechanism of HSPA8 in HDP progression. Herein, HSPA8 mRNA expression in placentas and peripheral blood of patients with HDP and normal pregnant controls was measured with RT-qPCR. We found that HSPA8 expression was downregulated in placentas and peripheral blood of patients with HDP. HTR8/SVneo human trophoblast cells were transfected with pcDNA-HSPA8 or si-HSPA8. HSPA8 overexpression promoted cell proliferation, migration, and MMP-2 and MMP-9 protein levels, and inhibited apoptosis, while HSPA8 silencing showed the opposite results. Co-immunoprecipitation assay validated the binding between HSPA8 and β-arrestin1, as well as β-arrestin1 and A1AR proteins. HSPA8 bound with β-arrestin1 protein and promoted β-arrestin1 expression. β-arrestin1 bound with A1AR protein and inhibited A1AR expression. Then, HTR8/SVneo cells were transfected with pcDNA-HSPA8 alone or together with si-β-arrestin1, as well as transfected with pcDNA-β-arrestin1 alone or together with pcDNA-A1AR. β-arrestin1 silencing reversed the effects of HSPA8 overexpression on HTR8/SVneo cell functions. β-arrestin1 overexpression promoted cell proliferation migration, and MMP-2 and MMP-9 protein levels, and inhibited apoptosis, while these effects were reversed by A1AR overexpression. Lentivirus HSPA8 overexpression vector (Lv-HSPA8) was injected into a preeclampsia (PE) rat model, which attenuated blood pressure and fetal detrimental changes in PE rats. In conclusion, HSPA8 promoted proliferation and migration and inhibited apoptosis in trophoblast cells, and attenuated the symptoms of PE rats by modulating the β-arrestin1/A1AR axis. Our study provided a novel theoretical evidence and potential strategy for HDP treatment.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, the Second Affiliated Hospital of Zhengzhou University, No. 2, Jingba Road, Jinshui District, Zhengzhou, 450014, Henan Province, China

    Ke Zhang, Hailing Zhang, Fang Wang, Shanshan Gao & Caiping Sun

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  1. Ke Zhang
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  2. Hailing Zhang
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  3. Fang Wang
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Contributions

KZ designed the experiments. KZ, HZ, FW, and SG performed the experimental work. CS provided statistical analysis as well as figures and table for the manuscript. KZ wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Ke Zhang.

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Ethics Approval

This study was approved by the Ethnic Committee of the Second Affiliated Hospital of Zhengzhou University. All animal care and experimental procedures in this study were approved by Animal Care and Use Committee of the Second Affiliated Hospital of Zhengzhou University.

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This study was approved by the Ethnic Committee of the Second Affiliated Hospital of Zhengzhou University, and all subjects had read and signed the informed consent.

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All authors have written the informed consent for publication.

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The authors declare no competing interests.

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Zhang, K., Zhang, H., Wang, F. et al. HSPA8 Is Identified as a Novel Regulator of Hypertensive Disorders in Pregnancy by Modulating the β-Arrestin1/A1AR Axis. Reprod. Sci. 29, 564–577 (2022). https://doi.org/10.1007/s43032-021-00719-8

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  • DOI: https://doi.org/10.1007/s43032-021-00719-8

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