SIRT1-mediated deacetylation of NF-κB inhibits the MLCK/MLC2 pathway and the expression of ET-1, thus alleviating the development of coronary artery spasm

Abstract

Coronary artery spasm (CAS) is an intense vasoconstriction of coronary arteries that cause total or subtotal vessel occlusion. The cardioprotective effect of sirtuin-1 (SIRT1) has been extensively highlighted in coronary artery diseases. The aims within this study include the investigation of the molecular mechanism by which SIRT1 alleviates CAS. SIRT1 expression was first determined by RT-qPCR and Western blot analysis in an endothelin-1 (ET-1)-induced rat CAS model. Interaction among SIRT1, nuclear factor-kappaB (NF-κB), myosin light chain kinase/myosin light chain-2 (MLCK/MLC2), and ET-1 was analyzed using luciferase reporter assay, RT-qPCR and Western blot analysis. After ectopic expression and depletion experiments in vascular smooth muscle cells (VSMCs), contraction and proliferation VSMCs, and expression of contraction-related proteins (α-SMA, calponin, and SM22α) were measured by collagen gel contraction, EdU assay, RT-qPCR and Western blot analysis. The obtained results showed that SIRT1 expression was reduced in rat CAS models. However, overexpression of SIRT1 inhibited the contraction and proliferation of VSMCs in vitro. Mechanistic investigation indicated that SIRT1 inhibited NF-κB expression through deacetylation. Moreover, NF-κB could activate the MLCK/MLC2 pathway and up-regulate ET-1 expression by binding to their promoter regions, thus inducing VSMC contraction and proliferation in vitro. In vivo experimental results also revealed that SIRT1 alleviated CAS through regulation of the NF-κB/MLCK/MLC2/ET-1 signaling axis. Collectively, our data suggested that SIRT1 could mediate the deacetylation of NF-κB, disrupt the MLCK/MLC2 pathway and inhibit the expression of ET-1 to relieve CAS, providing a theoretical basis for the prospect of CAS treatment and prevention.

Dexmedetomidine prevents cardiomyocytes from hypoxia/reoxygenation injury via modulating tetmethylcytosine dioxygenase 1-mediated DNA demethylation of Sirtuin1

“…Absent in melanoma 2 (AIM2) restrains the acetylation of NF-κB by interacting with signal transducer and activator of transcription 1 (STAT1) phosphorylation, thereby reducing the transcription of inflammatory factors in cardiac myocytes [ 51 ]. In addition, Sirt1-mediated NF-κB deacetylation hinders the myosin light-chain kinase/myosin light chain-2 (MLCK/MLC2) pathway and endothelin-1 (ET-1) expression, thus alleviating coronary artery spasm [ 52 ]. Pterostilbene (PTE) abates NF-κB acetylation in BV-2 microglia through up-regulation of Sirt1, thereby choking the expression of inflammatory factors [ 53 ].…”

Downregulation of connexin 43-based gap junctions underlies propofol-induced excessive relaxation in hypertensive vascular smooth muscle cells

“…As reported, both the RhoA/LIMK2/cofolin and RhoA/MLCK pathways can lead to cell contraction [ 15 , 24 ]. Our results demonstrated that Ang II exposure significantly activated the RhoA/LIMK2/cofilin and RhoA/MLCK signaling pathways, manifested as an increase in key molecules, such as p-LIMK2, p-cofilin and MLCK, which was reversed by propofol and Rhosin (Fig.…”

“…Activated RhoA can stimulate LIMK2 and cofilin phosphorylation,inhibit the degradation of the F-actin cytoskeleton and lead to stable cell contraction [ 15 ]. RhoA activation also inhibits the function of myosin light chain phosphatase, which is responsible for the dephosphorylation of MLC2, and thus keeps MLC2 phosphorylated [ 24 ]. In addition, the interaction between actin and myosin is implicated in vasoconstriction [ 25 , 26 ].…”

Bergamottin alleviates LPS-induced acute lung injury by inducing SIRT1 and suppressing NF-κB

“…It has been documented that SIRT1 is involved in deacetylation of NF-κB and inhibition of NF-κB activation. 21 , 22 Next, we checked whether bergamottin could promote SIRT1 expression to inhibit NF-κB signaling. LPS stimulation decreased the mRNA level of SIRT1 in the lung tissues of mice ( Figure 5C ).…”