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Angiotensin II Promotes KV7.4 Channels Degradation Through Reduced Interaction With HSP90 (Heat Shock Protein 90)

Greenwood, IA; Barrese, V; Stott, J; Figueiredo, H (2018) Angiotensin II Promotes KV7.4 Channels Degradation Through Reduced Interaction With HSP90 (Heat Shock Protein 90). HYPERTENSION, 71 (6). pp. 1091-1100. ISSN 0194-911X https://doi.org/10.1161/HYPERTENSIONAHA.118.11116
SGUL Authors: Greenwood, Iain Andrew

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Abstract

Voltage-gated Kv7.4 channels have been implicated in vascular smooth muscle cells’ activity because they modulate basal arterial contractility, mediate responses to endogenous vasorelaxants, and are downregulated in several arterial beds in different models of hypertension. Angiotensin II (Ang II) is a key player in hypertension that affects the expression of several classes of ion channels. In this study, we evaluated the effects of Ang II on the expression and function of vascular Kv7.4. Western blot and quantitative polymerase chain reaction revealed that in whole rat mesenteric artery, Ang II incubation for 1 to 7 hours decreased Kv7.4 protein expression without reducing transcript levels. Moreover, Ang II decreased XE991 (Kv7)–sensitive currents and attenuated membrane potential hyperpolarization and relaxation induced by the Kv7 activator ML213. Ang II also reduced Kv7.4 staining at the plasma membrane of vascular smooth muscle cells. Proteasome inhibition with MG132 prevented Ang II–induced decrease of Kv7.4 levels and counteracted the functional impairment of ML213-induced relaxation in myography experiments. Proximity ligation assays showed that Ang II impaired the interaction of Kv7.4 with the molecular chaperone HSP90 (heat shock protein 90), enhanced the interaction of Kv7.4 with the E3 ubiquitin ligase CHIP (C terminus of Hsp70-interacting protein), and increased Kv7.4 ubiquitination. Similar alterations were found in mesenteric vascular smooth muscle cells isolated from Ang II–infused mice. The effect of Ang II was emulated by 17-AAG (17-demethoxy-17-(2-propenylamino) geldanamycin) that inhibits HSP90 interactions with client proteins. These results show that Ang II downregulates Kv7.4 by altering protein stability through a decrease of its interaction with HSP90. This leads to the recruitment of CHIP and Kv7.4 ubiquitination and degradation via the proteasome.

Item Type: Article
Additional Information: This is a non-final version of an article published in final form in Greenwood, IA; Barrese, V; Stott, J; Figueiredo, H (2018) Angiotensin II Promotes KV7.4 Channels Degradation Through Reduced Interaction With HSP90 (Heat Shock Protein 90). Hypertension. 2018;71:1091-1100
Keywords: Cardiovascular System & Hematology, 1103 Clinical Sciences, 1102 Cardiovascular Medicine And Haematology
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: HYPERTENSION
ISSN: 0194-911X
Dates:
DateEvent
June 2018Published
23 April 2018Published Online
22 March 2018Accepted
Publisher License: Publisher's own licence
Projects:
Project IDFunderFunder ID
MR/K019074/1Medical Research Councilhttp://dx.doi.org/10.13039/501100000265
PG/15/97/31862British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
FS/14/33/30799British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
RG/16/7/32357British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
CF16-0136Carlsberg Foundation FellowshipUNSPECIFIED
URI: http://sgultest.da.ulcc.ac.uk/id/eprint/109737
Publisher's version: https://doi.org/10.1161/HYPERTENSIONAHA.118.11116

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