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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Experimental Pharmacology and Drug Discovery
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1496393
This article is part of the Research Topic Therapeutic Effects of Endogenous Hormones in Pathologies Linked to Metabolic and/or Inflammatory Disorders View all articles

Molecular Mechanism Underlying Cardioprotective Effect of Dehydroepiandrosterone on Endoplasmic Reticulum Stress Induced Apoptosis in Human Vascular Smooth Muscle Cells and Human Umbilical Vein Endothelial Cells

Provisionally accepted
Ye Zhu Ye Zhu 1Junxiu Wei Junxiu Wei 2*Xin Yang Xin Yang 1*Wei Zhu Wei Zhu 3*
  • 1 Peking University People's Hospital, Beijing, China
  • 2 Affiliated Hospital of Hebei University, Baoding, Hebei Province, China
  • 3 Mudanjiang Medical University, Mudanjiang, China

The final, formatted version of the article will be published soon.

    Abstract Introduction: This study aimed to investigate the underlying mechanisms involved in the cardioprotective effects of dehydroepiandrosterone (DHEA) on endoplasmic reticulum stress (ERS) -mediated apoptosis in human vascular smooth muscle cells (HVSMCs) and human umbilical vein endothelial cells (HUVECs). Material and Methods: Various concentrations of Dithiothreitol (DTT) were used to induce ERS-mediated apoptosis. DHEA was utilized to inhibit the apoptotic effects of DTT, while estrogen receptor (ER) antagonists ICI 182,780 and G15, the androgen receptor (AR) antagonist flutamide and the aromatase inhibitor letrozole were used to identify the receptors activated during DHEA treatment in HVSMCs and HUVECs. Flow cytometry assessed the apoptotic rate, and Western blotting analysis evaluated the expression levels of ERS-related proteins GRP78 and PERK, and the apoptotic protein marker CHOP. Furthermore, the primary receptor signaling pathways were identified using signaling pathway blockers: LY294002 (PI3K blocker), SP600125 (JNK blocker), and U0126 (ERK1/2 blocker). Results: In the DTT pretreatment group (0.8 mmol/L, for 8 hours), the expressions of GRP78 and CHOP were significantly up regulated, indicating that an optimal ERS model was successfully established. Additionally, 10-4 mmol/L DHEA significantly inhibited the DTT-induced up-regulation of GRP78 and CHOP. The results also demonstrated that the apoptotic rate in the DTT group was increased, while DHEA significantly reduced this rate. The addition of ER antagonists ICI 182,780 and G15 to HVSMCs reversed the effects of DHEA; however, the aromatase inhibitor letrozole and the AR antagonist flutamide did not reverse this effect. Notably, the use of the JNK inhibitor SP600125, the PI3K inhibitor LY294002, and the ERK1/2 inhibitor U0126 antagonized the protective effects of DHEA, with SP600125 showing the most significant impact on both HVSMCs and HUVECs. Conclusion: Our study has identified a novel mechanism underlying the cardioprotective effects of DHEA. Specifically, DHEA may mitigate ERS-induced cell apoptosis by activating estrogen receptors ERα, ERβ, and GPER via the activated JNK pathway.

    Keywords: Apoptosis, Dehydroepiandrosterone, Endoplasmic Reticulum Stress, Human vascular smooth muscle cells, Human Umbilical Vein Endothelial Cells

    Received: 14 Sep 2024; Accepted: 10 Jan 2025.

    Copyright: © 2025 Zhu, Wei, Yang and Zhu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Junxiu Wei, Affiliated Hospital of Hebei University, Baoding, Hebei Province, China
    Xin Yang, Peking University People's Hospital, Beijing, China
    Wei Zhu, Mudanjiang Medical University, Mudanjiang, China

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