Modulation of the LKB1-AMPK Signalling Pathway Underpins Hypoxic Pulmonary Vasoconstriction and Pulmonary Hypertension

Abstract

Perhaps the defining characteristic of pulmonary arteries is the process of hypoxic pulmonary vasoconstriction (HPV) which, under physiological conditions, supports ventilation-perfusion matching in the lung by diverting blood flow away from oxygen deprived areas of the lung to oxygen rich regions. However, when alveolar hypoxia is more widespread, either at altitude or with disease (e.g., cystic fibrosis), HPV may lead to hypoxic pulmonary hypertension. HPV is driven by the intrinsic response to hypoxia of pulmonary arterial smooth muscle and endothelial cells, which are acutely sensitive to relatively small changes in pO2 and have evolved to monitor oxygen supply and thus address ventilation-perfusion mismatch. There is now a consensus that the inhibition by hypoxia of mitochondrial oxidative phosphorylation represents a key step towards the induction of HPV, but the precise nature of the signalling pathway(s) engaged thereafter remains open to debate. We will consider the role of the AMP-activated protein kinase (AMPK) and liver kinase B1 (LKB1), an upstream kinase through which AMPK is intimately coupled to changes in oxygen supply via mitochondrial metabolism. A growing body of evidence, from our laboratory and others, suggests that modulation of the LKB1-AMPK signalling pathway underpins both hypoxic pulmonary vasoconstriction and the development of pulmonary hypertension.

Protein expression profile changes of lung tissue in patients with pulmonary hypertension

“…AMPK is activated by an increase in the ratio of ADP to ATP and rapidly amplifies the signaling pathway in synergy with LKB1, maintaining the intracellular ATP concentration by catabolism and inhibition of unnecessary ATP depletion. Therefore, AMPK regulates the mitochondrial energy balance and maintains the energy supply of smooth muscle cells during hypoxia to preserve normal physiological functions (Evans et al, 2015). In the present study, the expression of AMPKα1 was significantly increased in the lung tissue of patients with pulmonary hypertension.…”

“…Under hypoxic conditions, lactate dehydrogenase activity is increased after AMPK activity is inhibited by the AMPK antagonist compound C, leading to the induction of apoptosis in smooth muscle cells (Ibe et al, 2013). Evans et al (2015) have suggested that the levels of AMPK and liver kinase B1 (LKB1) are upregulated when mitochondria sense a change in the oxygen supply. These upregulated levels cause a sustained blood vessel contraction through an LKB1-AMPK signaling pathway and result in continuous pulmonary hypertension.…”

Hypoxic Pulmonary Vasoconstriction in Humans: Tale or Myth

“…Similarly Evans et al . proved that inhibition of oxidative phosphorylation in mitochondria through LKB1 (liver kinase B1) – AMPK (amp activated protein kinase) signalling pathway triggers hypoxic pulmonary vasoconstriction [ 72 ]. This demonstration of hypoxia induced mitochondrial dysfunction in pulmonary artery endothelium, smooth muscle and adventitia of pulmonary hypertension patients suggests that production of targeted mitochondrial therapies will provide effective therapy for this life threatening disease [ 73 , 74 ]…”

Elevated galectin-3 level predicts pulmonary artery hypertension

“…Indeed, despite the pathogenesis of PAH is a complex and multifactorial process, inflammation could be a trigger of endothelial injury, pulmonary artery smooth muscle cell proliferation, chemoattractant over-production [4]. There is evidence regarding the role of pulmonary arterial smooth muscle and endothelial cells in vasoconstriction, development of vaso-occlusive lesions and ventilation-perfusion mismatch [31]. Therefore, PAH might occur due to several molecular mechanisms resulting in heterogeneous genetic defects affecting defects of the transforming growth factor beta pathway that could be regulated with Gal-3 [32].…”