2. Academic Validation
  3. Hydrogen sulfide ameliorated endothelial dysfunction in hyperhomocysteinemia rats: Mechanism of IRE1α/JNK pathway-mediated autophagy

Hydrogen sulfide ameliorated endothelial dysfunction in hyperhomocysteinemia rats: Mechanism of IRE1α/JNK pathway-mediated autophagy

  • Nitric Oxide. 2024 Dec 1:153:72-81. doi: 10.1016/j.niox.2024.10.008.
Yuan Gao 1,  Jiao Xu 2,  Kaichuan He 3,  Qi Guo 4,  Lin Xiao 2,  Sheng Jin 2,  Danyang Tian 2,  Xu Teng 2,  Cuixia An 5,  Hongmei Xue 6,  Yuming Wu 7
Affiliations

Affiliations

  • 1 Department of Physiology, Institute of Basic Medicine, Hebei Medical University, 050017, Hebei, China; Department of Physiology, Institute of Basic Medicine, Xingtai Medical College, 054000, Hebei, China.
  • 2 Department of Physiology, Institute of Basic Medicine, Hebei Medical University, 050017, Hebei, China.
  • 3 Department of Physiology, Institute of Basic Medicine, Hebei Medical University, 050017, Hebei, China; Hebei Key Laboratory of Metabolic Diseases, Center for Clinical Medical Research, Hebei General Hospital, 050051, Hebei, China.
  • 4 Experimental Center for Teaching, Hebei Medical University, 050017, Hebei, China.
  • 5 Department of Psychiatry, The First Hospital of Hebei Medical University, 050031, Hebei, China.
  • 6 Department of Physiology, Institute of Basic Medicine, Hebei Medical University, 050017, Hebei, China. Electronic address: hmxue@hebmu.edu.cn.
  • 7 Department of Physiology, Institute of Basic Medicine, Hebei Medical University, 050017, Hebei, China; Hebei Key Laboratory of Cardiovascular Homeostasis and Aging, 050017, Hebei, China; The Key Laboratory of Neural and Vascular Biology, Ministry of Education, 050017, Hebei, China; Hebei Collaborative Innovation Center for Cardio-Cerebrovascular Disease, 050017, Hebei, China. Electronic address: wuym@hebmu.edu.cn.
PMID: 39396802 DOI: 10.1016/j.niox.2024.10.008
Abstract

Previous studies showed that hyperhomocysteinemia (HHcy) induced endothelial dysfunction by endoplasmic reticulum (ER) stress induction and Autophagy stimulation. This study aimed to determine the effect of hydrogen sulfide (H2S) in homocysteine (Hcy)-induced endothelial dysfunction and observe the possible mechanism involved. Male Wistar rats (160-180g) were used and randomly divided into four groups: Control group, HHcy group, HHcy+Sodium hydrosulfide (NaHS) group and NaHS group. Rats were fed with 2% high methionine diet for 8 weeks to set up HHcy model. Plasma concentration of Hcy was measured by ELISA. Endothelium-dependent and non-endothelium-dependent vasodilation of rat renal arteries were determined by myograph. The protein expression of cystathionine-γ-lyase (CSE), ER stress- and autophagy-related proteins in renal arteries or human umbilical vein endothelial cells (HUVECs) were analyzed by western blotting. The endothelial function was impaired in HHcy rats and HUVECs. NaHS supplementation could improve the ACh-induced vasodilation, however it was eliminated by ER stress inducer Tunicamycin (TM) or Autophagy inducer Rapamycin. Western blotting in renal arteries showed that Glucose-regulated protein 78 (GRP78) and three branches of ER stress (p-IRE1α, p-PERK, ATF6) , p-JNK1+p-JNK2 were downregulated, simultaneously the Autophagy marker Beclin1, LC3BII/LC3BI ratio were decreased and p62 was increased with NaHS treatment in HHcy rats. In HUVECs, IRE1α-JNK induced Autophagy was involved in HHcy-induced endothelial dysfunction, while NaHS stimulation reversed the protein expression in IRE1α/JNK-autophagy pathway with Hcy incubation. This study might suggest that endothelial dysfunction induced by HHcy might be correlated with IRE1α-JNK-autophagy axis pathway, which was suppressed by exogenous supplementation of H2S donor, NaHS.

Keywords

Autophagy; Endoplasmic reticulum stress; Endothelial dysfunction; Hydrogen sulfide; Hyperhomocysteinemia; Methionine.

Figures
Products
Inhibitors & Agonists
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15845
    ≥98.0%, IRE1 Inhibitor