Details

Autor(en) / Beteiligte

• Fancher, Ibra S
• Chignalia, Andreia Z
• Isbatan, Ayman
• Phillips, Shane A
• Dull, Randal O
• Levitan, Irena

Titel

Abstract 16551: Shear-Induced Kir2.1 Channel Activation is Mediated Through Interactions With Syndecan-1

Ist Teil von

• Circulation (New York, N.Y.), 2018-11, Vol.138 (Suppl_1 Suppl 1), p.A16551-A16551

Ort / Verlag

by the American College of Cardiology Foundation and the American Heart Association, Inc

Erscheinungsjahr

2018

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Inwardly rectifying K+ (Kir) channels are known to be sensitive to flow and proposed to play a major role in endothelial mechanotransduction. We recently identified a critical role for endothelial Kir2.1 channels in regulating flow-mediated dilations through Akt-1 and eNOS activation. We also showed that severely dyslipidemic mice deficient in Kir2.1 expression had increased lesion formation in otherwise atheroprotected areas of the aorta (e.g. descending aorta) compared to dyslipidemic mice with normal Kir2.1 expression. In the current study, we explore the mechanism responsible for the sensitivity of Kir to flow. First, we show that removal of heparan sulfates using Heparinase III (HepIII) from the endothelial glycocalyx, a major mechanosensor network, abrogates the sensitivity of Kir channels to flow. This is established using perforated patch clamp performed on freshly isolated mesenteric endothelial cells (ECs) seeded into a minimally invasive flow device that allows for applying well-defined laminar flow across ECs during electrophysiological recordings. As expected, we detected an average 20% increase in inwardly rectifying K current (IKir) from ECs exposed to flow (0.7 dynes/cm), whereas no increase was observed in cells treated with HepIII. Furthermore, focusing on syndecan-1 (sdc-1), which was shown to be involved in flow-induced activation of Akt-1 and in maintaining the atheroprotective phenotype, we found that sdc1 plays an important role in flow activation of Kir. Comparing freshly isolated mesenteric ECs from WT and sdc-1 KO mice revealed that flow-induced increases in IKirwere significantly reduced as was the time to IKirsaturation in ECs isolated from sdc-1 mice, suggesting that sdc-1 plays a role in mediating flow-induced activation of Kir2.1. Co-immunoprecipitation revealed a physical interaction between sdc-1 and Kir2.1 that may be partially mediated by heparin sulfates as a reduced interaction was detected in human aortic endothelial cell lysates treated with HepIII. We propose that Kir channel activation is coupled to sdc1 and downstream endothelial responses to flow.