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.
Highlights
Medial vascular calcification (VC) is frequently observed in patients with chronic kidney disease (CKD), and it increases the incidence of cardiovascular events and mortality.[1]
Inhibition of sirt1 reduced the effect of terpinen-4-ol on the deacetylation of protein kinase RNA-like ER kinase (PERK) in vitro and in vivo and weakened the inhibitory effect of terpinen-4-ol against Endoplasmic reticulum (ER) stress-mediated VC
Terpinen-4-ol inhibits the post-transcriptional modification of PERK at the lysine K889 acetylation site by upregulating sirt1 expression level, thereby ameliorating VC by regulating ER stress. This provides evidence of the molecular mechanism of terpinen-4-ol, which supports its development as a promising therapeutic agent for CKD-VC
Summary
Medial vascular calcification (VC) is frequently observed in patients with chronic kidney disease (CKD), and it increases the incidence of cardiovascular events and mortality.[1] VC promotes stiffness of the vascular wall, resulting in increased pulse pressure, left ventricular hypertrophy, and heart failure.[2] Studies have identified the phenotypic switching of vascular smooth muscle cells (VSMCs) as a key event in VC. Phosphorylated eIF2α can activate downstream activating transcription factor 4 (ATF4) in the nucleus to promote the phenotypic transformation of VSMCs, thereby promoting the development of VC.[10,11,12] the exact molecular mechanism of PERK-eIF2α-ATF4 signaling in CKD-dependent VC is still unclear. 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). 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
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