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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Wen-Tao Sun1, Xiang-Chong Wang1, Shiu-Kwong Mak1, Guo-Wei He2, Xiao-Cheng Liu2, Malcolm John Underwood3 and Qin Yang1,2
1Division of Cardiology, Department of Medicine and Therapeutics, Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, Institute of Innovative Medicine, The Chinese University of Hong Kong, Hong Kong, China
2TEDA International Cardiovascular Hospital, Chinese Academy of Medical Sciences, Tianjin, China
3Division of Cardiothoracic Surgery, Department of Surgery, The Chinese University of Hong Kong, Hong Kong, China
Qin Yang, email: [email protected]
Keywords: cardiovascular risk factors, coronary circulation, endoplasmic reticulum stress, homocysteine, smooth muscle cell
Received: November 08, 2016 Accepted: April 07, 2017 Published: May 09, 2017
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 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 BKCachannel 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.
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