Activation of PERK branch of ER stress mediates homocysteine-induced BKCa channel dysfunction in coronary artery via FoxO3a-dependent regulation of atrogin-1
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AbstractThe molecular mechanism of endoplasmic reticulum (ER) stress in vascular pathophysiology remains inadequately understood. We studied the role of ER stress in homocysteine-induced impairment of coronary dilator function, with uncovering the molecular basis of the effect of ER stress on smooth muscle large-conductance Ca2+-activated K+ (BKCa) channels. The vasodilatory function of BKCa channels was studied in a myograph using endothelium-denuded porcine small coronary arteries. Primary cultured porcine coronary artery smooth muscle cells were used for mRNA and protein measurements and current recording of BKCa channels. Homocysteine inhibited vasorelaxant response to the BKCa channel opener NS1619, lowered BKCa β1 subunit protein level and suppressed BKCa current. Inhibition of ER stress restored BKCa β1 protein level and NS1619-evoked vasorelaxation. Selective blockade of the PKR-like ER kinase (PERK) yielded similarly efficient restoration of BKCa β1, preserving BKCa current and BKCa-mediated vasorelaxation. The restoration of BKCa β1 by PERK inhibition was associated with reduced atrogin-1 expression and decreased nuclear localization of forkhead box O transcription factor 3a (FoxO3a). Silencing of atrogin-1 prevented homocysteine-induced BKCa β1 loss and silencing of FoxO3a prevented atrogin-1 upregulation induced by homocysteine, accompanied by preservation of BKCa β1 protein level and BKCa current. ER stress mediates homocysteine-induced BKCa channel inhibition in coronary arteries. Activation of FoxO3a by PERK branch underlies the ER stress-mediated BKCa inhibition through a mechanism involving ubiquitin ligase-enhanced degradation of the channel β1 subunit.
All Author(s) ListWen-Tao Sun, Xiang-Chong Wang, Shiu-Kwong Mak, Guo-Wei He, Xiao-Cheng Liu, Malcolm John Underwood, Qin Yang
Journal nameOncotarget
Volume Number8
Issue Number31
PublisherImpact Journals
Pages51462 - 51477
LanguagesEnglish-United Kingdom

Last updated on 2021-20-09 at 00:27