Role of adenylate kinase 4 as a new metabolic regulator of pulmonary artery smooth muscle cells under hypoxia

Introduction: Excessive proliferation of pulmonary artery smooth muscle cells (PASMC) is one of key components of the vascular remodeling in chronic hypoxic pulmonary hypertension (PH). Adenylate kinase 4 (AK4), a hypoxia-responsive mitochondrial enzyme, was recently shown to promote metabolic reprogramming and lung cancer metastasis. Aim: In view of emerging cancer-like and metabolic theories of PH, we aimed to characterize the role of AK4 in PASMC responses to hypoxia to shed light on the importance of AK4 in the pathogenesis of PH. Results: Exposure of human and mouse PASMC to hypoxia increased the expression of AK4. AK4 was also upregulated in lungs of mice with hypoxia-induced PH and in PASMC following the stimulation with transforming growth factor-β1 (TGF-β1), which is implicated in the pathogenesis of PH. The functional role of AK4 was further tested in mouse PASMC, demonstrating that AK4 downregulation increased the proliferation of PASMC when exposed to hypoxia or treated with TGF-β1. AK4 downregulation resulted in an activation of cyclin D1/ERK1/2 signalling pathway, increased levels of mitochondrial respiratory chain complexes III and IV, and decreased activation of AMP-activated protein kinase (AMPK), which has been considered as a potential therapeutic target for the treatment of PH. Conclusions: Our data suggest that increased AK4 expression might serve as a protective mechanism for regulation of a proliferative and metabolic phenotype of PASMC under hypoxia. We acknowledge the support of the European Respiratory Society, and the Deutsches Zentrums für Lungenforschung, (Fellowship LTRF 2018), and the German Research Foundation, Project no. 268555672-SFB1213.