Role for NADH-sensitive KV channels in the myocardial-vascular signaling axis

Role for NADH-sensitive KV channels in the myocardial-vascular signaling axis

Nystoriak M;Ohanyan V;Dwenger M;Chilian W;Bhatnagar A

Faseb Journal

2020

2020-04

Voltage‐gated potassium (Kv) channels expressed in the coronary vasculature play a pivotal role in coupling oxygen delivery with myocardial metabolic demand. Despite their importance in maintaining adequate perfusion to support proper cardiac function, the processes by which these channels respond to metabolic cues from the myocardium to elicit smooth muscle hyperpolarization and rapid relaxation are unclear. We tested the hypothesis that the heteromeric auxiliary Kvβ subunit (Kvβ1:Kvβ2) complex facilitates increases in Kv1 channel activity and coronary vasodilation during periods of elevated myocardial oxygen consumption. The Kvβ proteins are functional aldo‐keto reductases, and thus catalyze nicotinamide cofactor‐ (i.e., NAD(P)H) dependent reduction of a range of aldehyde substrates. Intriguingly, these subunits also differentially modify the voltage‐sensitivity of Kv1 channels in a manner that depends upon the redox state of bound cofactor. Imaging mass spectrometry revealed that lactate:pyruvate (used as a surrogate for NADH:NAD+) was significantly increased in intramyocardial arteries in hearts from mice acutely treated with dobutamine to drive elevated cardiac workload versus those from vehicle‐treated mice. Elevation of NADH:NAD+ ratio in coronary arterial myocytes following perfusion of sodium lactate reversibly increased whole cell Kv currents and shifted the voltage‐dependence of activation by −15 mV. Moreover, application of 1 mM NADH, but not NAD+, increased single Kv1 channel currents in excised membrane patches from coronary arterial myocytes of wild type mice. In contrast, ablation of Kvβ2 abolished the NADH sensitivity of Kv1 activity, whereas ablation of Kvβ1 had little effect. Consistent with this, we found that vasodilation of coronary arteries to reduced bath oxygen (to 3%) and the relationship between cardiac work and myocardial blood flow was significantly blunted in Kvβ2−/− arteries/mice when compared with wild type arteries/mice. Together, our results suggest that the Kvβ complex is a functional sensing unit that modulates native coronary Kv1 channel activity upon changes in pyridine nucleotide redox ratio, which may impart a profound influence on the control of myocardial blood flow.

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journalArticle

1

34

0892-6638

NEOMED College of Medicine

Department of Integrative Medicine

September 2020 List