Faculty Collaboration Database

Contribution of K_V1.5 Channel to Hydrogen Peroxide-Induced Human Arteriolar Dilation and Its Modulation by Coronary Artery Disease. Circ Res 2017 Feb 17;120(4):658-669

Date

11/23/2016

Pubmed ID

27872049

Pubmed Central ID

PMC5315616

DOI

10.1161/CIRCRESAHA.116.309491

Scopus ID

2-s2.0-85000399498 (requires institutional sign-in at Scopus site)   43 Citations

Abstract

RATIONALE: Hydrogen peroxide (H₂O₂) regulates vascular tone in the human microcirculation under physiological and pathophysiological conditions. It dilates arterioles by activating large-conductance Ca²⁺-activated K⁺ channels in subjects with coronary artery disease (CAD), but its mechanisms of action in subjects without CAD (non-CAD) when compared with those with CAD remain unknown.

OBJECTIVE: We hypothesize that H₂O₂-elicited dilation involves different K⁺ channels in non-CAD versus CAD, resulting in an altered capacity for vasodilation during disease.

METHODS AND RESULTS: H₂O₂ induced endothelium-independent vasodilation in non-CAD adipose arterioles, which was reduced by paxilline, a large-conductance Ca²⁺-activated K⁺ channel blocker, and by 4-aminopyridine, a voltage-gated K⁺ (K_V) channel blocker. Assays of mRNA transcripts, protein expression, and subcellular localization revealed that K_V1.5 is the major K_V1 channel expressed in vascular smooth muscle cells and is abundantly localized on the plasma membrane. The selective K_V1.5 blocker diphenylphosphine oxide-1 and the K_V1.3/1.5 blocker 5-(4-phenylbutoxy)psoralen reduced H₂O₂-elicited dilation to a similar extent as 4-aminopyridine, but the selective K_V1.3 blocker phenoxyalkoxypsoralen-1 was without effect. In arterioles from CAD subjects, H₂O₂-induced dilation was significantly reduced, and this dilation was inhibited by paxilline but not by 4-aminopyridine, diphenylphosphine oxide-1, or 5-(4-phenylbutoxy)psoralen. K_V1.5 cell membrane localization and diphenylphosphine oxide-1-sensitive K⁺ currents were markedly reduced in isolated vascular smooth muscle cells from CAD arterioles, although mRNA or total cellular protein expression was largely unchanged.

CONCLUSIONS: In human arterioles, H₂O₂-induced dilation is impaired in CAD, which is associated with a transition from a combined large-conductance Ca²⁺-activated K⁺- and K_V (K_V1.5)-mediated vasodilation toward a large-conductance Ca²⁺-activated K⁺-predominant mechanism of dilation. Loss of K_V1.5 vasomotor function may play an important role in microvascular dysfunction in CAD or other vascular diseases.

Author List

Nishijima Y, Cao S, Chabowski DS, Korishettar A, Ge A, Zheng X, Sparapani R, Gutterman DD, Zhang DX

Authors

Rodney Sparapani PhD Associate Professor in the Institute for Health and Equity department at Medical College of Wisconsin
David X. Zhang MD, PhD Associate Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Arterioles
Cells, Cultured
Coronary Artery Disease
Coronary Vessels
Female
HEK293 Cells
Humans
Hydrogen Peroxide
Kv1.5 Potassium Channel
Male
Middle Aged
Muscle, Smooth, Vascular
Vasodilation