2. Academic Validation
  3. The ameliorative effect of terpinen-4-ol on ER stress-induced vascular calcification depends on SIRT1-mediated regulation of PERK acetylation

The ameliorative effect of terpinen-4-ol on ER stress-induced vascular calcification depends on SIRT1-mediated regulation of PERK acetylation

  • Pharmacol Res. 2021 Aug;170:105629. doi: 10.1016/j.phrs.2021.105629.
Yanyan Zhang 1,  Li He 2,  Mengxin Tu 1,  Mei Huang 2,  Yan Chen 3,  Di Pan 3,  Jianqing Peng 1,  Xiangchun Shen 4
Affiliations

Affiliations

  • 1 The State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, University Town, Guian New District, Guizhou, China; Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guizhou, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guizhou, China.
  • 2 The State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, University Town, Guian New District, Guizhou, China; Department of Pharmacology of Materia Medica (The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province), Guizhou Medical University, University Town, Guian New District, Guizhou, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guizhou, China.
  • 3 The State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, University Town, Guian New District, Guizhou, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guizhou, China.
  • 4 The State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, University Town, Guian New District, Guizhou, China; Department of Pharmacology of Materia Medica (The High Educational Key Laboratory of Guizhou Province for Natural Medicinal Pharmacology and Druggability, The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province), Guizhou Medical University, University Town, Guian New District, Guizhou, China; The Key Laboratory of Optimal Utilization of Natural Medicine Resources, School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guizhou, China. Electronic address: shenxiangchun@126.com.
PMID: 34089864 DOI: 10.1016/j.phrs.2021.105629
Abstract

Endoplasmic reticulum (ER) stress-mediated phenotypic switching of vascular smooth muscle cells (VSMCs) is key to vascular calcification (VC) in patients with chronic kidney disease (CKD). Studies have shown that activation/upregulation of SIRT1 has a protective effect on CKD-VC. Meanwhile, although terpinen-4-ol has been shown to exert a protective effect against Cardiovascular Disease, its role and underlying mechanism in VC remain unclear. Herein, we explored whether terpinen-4-ol alleviates ER stress-mediated VC through Sirtuin 1 (SIRT1) and elucidated its mechanism to provide evidence for its application in the clinical prevention and treatment of VC. To this end, a CKD-related VC animal model and β-glycerophosphate (β-GP)-induced VSMC calcification model were established to investigate the role of terpinen-4-ol in ER stress-induced VC, in vitro and in vivo. Additionally, to evaluate the involvement of SIRT1, mouse and VSMC Sirt1-knockdown models were established. Results show that terpinen-4-ol inhibits calcium deposition, phenotypic switching, and ER stress in VSMCs in vitro and in vivo. Furthermore, pre-incubation of VSMCs with terpinen-4-ol or a SIRT1 agonist, decreased β-GP-induced calcium salt deposition, increased SIRT1 protein level, and inhibited PERK-eIF2α-ATF4 pathway activation, thus, alleviating VC. Similar results were observed in VSMCs induced to overexpress SIRT1 via lentivirus transcription. Meanwhile, the opposite results were obtained in SIRT1-knockdown models. Further, results suggest that SIRT1 physically interacts with, and deacetylates PERK. Specifically, mass spectrometry analysis identified lysine K889 as the acetylation site of SIRT1, which regulates PERK. Finally, inhibition of SIRT1 reduced the effect of terpinen-4-ol on the deacetylation of PERK in vitro and in vivo and weakened the inhibitory effect of terpinen-4-ol against ER stress-mediated VC. Cumulatively, terpinen-4-ol was found to inhibit post-translational modification of PERK at the K889 acetylation site by upregulating SIRT1 expression, thereby ameliorating VC by regulating ER stress. This study provides insights into the underlying molecular mechanism of terpinen-4-ol, supporting its development as a promising therapeutic agent for CKD-VC.

Keywords

ER stress; PERK acetylation; SIRT1; Terpinen-4-ol; Vascular calcification.

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