AMPK-dependent modulation of breathing and oxygen supply: An emerging therapeutic strategy for sleep apnoea and pulmonary hypertension?

Abstract

Hypoxia triggers two reflexes that optimise breathing and oxygen supply: Hypoxic pulmonary vasoconstriction (HPV), mediated by mechanisms intrinsic to pulmonary arterial myocytes and endothelia, which aids ventilation-perfusion matching in the lungs by diverting blood flow from oxygen-deprived to oxygen-rich areas, but precipitates pulmonary hypertension when hypoxia is widespread at altitude or with disease (e.g. emphysema); The hypoxic ventilatory response (HVR), which is generally accepted to be triggered by the response to changing arterial oxygen saturation of carotid body glomus-cells, the primary arterial chemoreceptors. Our investigations suggest that the AMP-activated protein kinase (AMPK) mediates HPV and the HVR. Deletion of either the AMPK-alpha1 (PRKAA1) or AMPK-alpha2 (PRKAA2) gene in arterial myocytes blocks HPV and thus acute hypoxic pulmonary hypertension. By contrast. deletion of AMPK-aplha1 alone in catecholaminergic cells, including carotid body glomus-cells, blocks the HVR without affecting the carotid body afferent inputs, likely at a point downstream within brainstem respiratory networks. Moreover AMPK-alpha1 deficiency confers a neonate-like HVR incorporating hypoventilation and apnoea during hypoxia, suggesting that AMPK-alpha1 may protect against hypoxia-evoked ventilatory instability during sleep and at altitude. It would appear, therefore, that AMPK delivers system-level control of whole-body metabolic homeostasis by regulating oxygen supply, in a manner determined by the cell-specific expression patterns of AMPK subunits. The 12 heterotrimeric AMPK complexes formed by its 2 alpha (catalytic), 2 beta and 3 gamma (regulatory) subunits may therefore hold significant therapeutic potential for the treatment of pulmonary hypertension and sleep disordered breathing, given the availability of a growing number of new, subunit-selective small molecule modulators of AMPK.