AMPK-α1 or AMPK-α2 Deletion in Smooth Muscles Does Not Affect the Hypoxic Ventilatory Response or Systemic Arterial Blood Pressure Regulation During Hypoxia.

Sandy Macmillan,A Mark Evans

doi:10.3389/fphys.2018.00655

Abstract

The hypoxic ventilatory response (HVR) is markedly attenuated by AMPK-α1 deletion conditional on the expression of Cre-recombinase in tyrosine hydroxylase (TH) expressing cells, precipitating marked increases in apnea frequency and duration. It was concluded that ventilatory dysfunction caused by AMPK deficiency was driven by neurogenic mechanisms. However, TH is transiently expressed in other cell types during development, and it is evident that central respiratory depression can also be triggered by myogenic mechanisms that impact blood supply to the brain. We therefore assessed the effect on the HVR and systemic arterial blood pressure of AMPK deletion in vascular smooth muscles. There was no difference in minute ventilation during normoxia. However, increases in minute ventilation during severe hypoxia (8% O2) were, if affected at all, augmented by AMPK-α1 and AMPK-α2 deletion in smooth muscles; despite the fact that hypoxia (8% O2) evoked falls in arterial SpO2 comparable with controls. Surprisingly, these mice exhibited no difference in systolic, diastolic or mean arterial blood pressure during normoxia or hypoxia. We conclude that neither AMPK-α1 nor AMPK-α2 are required in smooth muscle for the regulation of systemic arterial blood pressure during hypoxia, and that AMPK-α1 deficiency does not impact the HVR by myogenic mechanisms.

Highlights

The AMP-activated protein kinase (AMPK) is a cellular energy sensor that maintains cellautonomous energy homeostasis
We investigated the possibility that AMPK-α1 or AMPK-α2 subunits might support myogenic responses to hypoxia and impact the hypoxic ventilatory response (HVR) and blood pressure control
Critical exons of the AMPK-α1 and -α2 subunit genes were flanked by loxP sequences (Lantier et al, 2014), and each floxed mouse line was crossed with mice expressing Cre recombinase under the control of the transgelin promoter (El-Bizri et al, 2008)

Summary

Introduction

The AMP-activated protein kinase (AMPK) is a cellular energy sensor that maintains cellautonomous energy homeostasis. AMPK is coupled to mitochondrial oxidative phosphorylation by two discrete albeit cooperative pathways, involving liver kinase B1 (LKB1) and changes in the cellular AMP:ATP and ADP:ATP ratios. Binding of AMP to the AMPK γ subunit increases activity 10-fold by allosteric activation alone, while AMP or ADP binding delivers increases in LKB1-dependent phosphorylation and reductions in dephosphorylation of Thr172 on the α. AMPK Blood Pressure and the HVR subunit that confer 100-fold further activation. All of these effects are inhibited by ATP (Gowans et al, 2013). There are alternative Ca2+dependent pathways to AMPK activation that are governed by the calmodulin-dependent protein kinase CaMKK2, which delivers increases in Thr172 phosphorylation and AMPK activation independent of changes in cellular AM(D)P:ATP ratios

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