Abstract
Adenosine monophosphate-activated protein kinase (AMPK) is a heterotrimeric serine-threonine kinase important as a metabolic sensor for intracellular ATP levels and plays a key role in regulating cell survival and proliferation, particularly when cells are exposed to hypoxia. AMPK is critical for lung function, and abnormal AMPK signaling participates in many lung diseases. Recent studies suggest that both inhibition and activation of AMPK are preventive for the development of pulmonary arterial hypertension (PAH). However, the molecular mechanisms by which inhibition or activation of AMPK affects pulmonary hypertension (PH) appear to be distinct. Inhibition of AMPK by compound C blocks hypoxia-induced autophagy and induces apoptosis in pulmonary artery smooth muscle cells, leading to prevention of PAH; activation of AMPK by metformin attenuates the PH phenotype induced by hypoxia by regulating endothelial cell function. These seemingly opposing data on the function of AMPK in PH can be partly explained by off-target and compartment-specific effects of AMPK inhibitors and activators and the differentiated expression of AMPK in various cell types and subcellular locations. To elucidate the specific roles of AMPK in the pathogenesis of PAH, it is important to study the role of AMPK in a tissue specific manner combining genetic and biochemical approaches.
Highlights
Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary arterial pressure that leads to right ventricular failure, and death [1,2]
The role of AMPK in lung, in pulmonary arterial hypertension (PAH), appears to be inconclusive: We have shown that AMPK inhibition is beneficial for the treatment of pulmonary hypertension (PH) [17] whereas others suggest that AMPK activators such as metformin and AICAR are protective against experimental PH [18]
We have suggested that inhibition of AMPK activity prevents and reverses hypoxiainduced PH by inducing PASMC death; on the other hand, Agard et al have suggested that activation of AMPK protects against hypoxia-induced PH, presumably by regulating endothelial cell function [18]
Summary
Pulmonary arterial hypertension (PAH) is a disease characterized by increased pulmonary arterial pressure that leads to right ventricular failure, and death. Pulmonary artery remodeling includes survival and proliferation of pulmonary artery smooth muscle cells (PASMC), which cause the development and progression of high pulmonary vascular tone observed in PAH patients [3]. Cell cycle regulation, decision to enter autophagy, apoptosis, and other cell fate decisions are regulated by AMPK (Figure 1) [9] In the lung, both isoforms of the catalytic α subunit are expressed [5,10,11]. Recent reports suggest that acute or moderate hypoxia can activate AMPK through Ca2+/calmodulin-dependent protein kinase kinase-β (CaMKKβ) independent of the AMP/ATP ratio [13,14,15]. We will present an overview on the current literature on the role of AMPK in PAH, analyze the causes of discrepancy, and discuss the future directions to elucidate the role of AMPK in the lung
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