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The 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 Ca 2+ -activated K + (BK Ca ) channels. The vasodilatory function of BK Ca 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 BK Ca channels. Homocysteine inhibited vasorelaxant response to the BK Ca channel opener NS1619, lowered BK Ca β1 subunit protein level and suppressed BK Ca current. Inhibition of ER stress restored BK Ca β1 protein level and NS1619-evoked vasorelaxation. Selective blockade of the PKR-like ER kinase (PERK) yielded similarly efficient restoration of BK Ca β1, preserving BK Ca current and BK Ca -mediated vasorelaxation. The restoration of BK Ca 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 BK Ca β1 loss and silencing of FoxO3a prevented atrogin-1 upregulation induced by homocysteine, accompanied by preservation of BK Ca β1 protein level and BK Ca current. ER stress mediates homocysteine-induced BK Ca channel inhibition in coronary arteries. Activation of FoxO3a by PERK branch underlies the ER stress-mediated BK Ca inhibition through a mechanism involving ubiquitin ligase-enhanced degradation of the channel β1 subunit.

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Activation of PERK branch of ER stress mediates homocysteine-induced BKCa channel dysfunction in coronary artery via FoxO3a-dependent regulation of atrogin-1