A06
Sensing and signaling events underlying development and recovery of hypoxia-induced pulmonary hypertension
Acute lung alveolar hypoxia triggers the physiological response of hypoxic pulmonary vasoconstriction (HPV) in order to match local perfusion to ventilation. HPV thus optimizes systemic arterial oxygenation and prevents hypoxemia under conditions of local alveolar hypoxia, e.g., during pneumonia or chronic pulmonary obstructive disease. However, under global and prolonged alveolar hypoxia, such as in high altitude or chronic lung diseases, prolonged HPV may contributed to increased pulmonary vascular resistance, leading to pulmonary hypertension (PH). Moreover, chronic hypoxia induces structural changes of the pulmonary vasculature, promoting PH and subsequent right ventricular failure. HPV and pulmonary vascular remodeling are reversible upon re-exposure to normoxia. We have previously shown that HPV is triggered by an increase of mitochondrial reactive oxygen species (ROS) while chronic hypoxia-induced pulmonary vascular remodeling is associated with decreased ROS in the pulmonary vasculature. We identified essential mechanisms triggering HPV and the paradoxical ROS release in acute hypoxia. In particular, we uncovered the essential relevance of the lung-specific isoform 2 of subunit 4 of the cytochrome c oxidase (Cox4i2). Cox4i2 may act as a universal oxygen sensing component, as we (in co-operation with Prof. Lopez-Barneo, Spain) found it also to be essential for acute oxygen sensing in the carotid body. Cox4i2 sensitizes the electron transport chain to hypoxia-induced redox changes of downstream components, in particular an increase of ubiquinol, and thus increased ROS release at complex III. We showed that Cox4i2 is not only expressed in pulmonary arterial smooth muscle cells (PASMC) but is also highly expressed in pulmonary pericyte-like cells together with other putative oxygen sensing candidates. In contrast, we largely excluded a role of Nox4 and NoxO1-containing NADPH oxidase derived ROS for acute oxygen sensing. Regarding chronic hypoxia-induced PH, we found that PTEN-induced kinase 1 (PINK1)-regulated mitophagy mediated hypoxia-induced proliferation and apoptosis of PASMC in vitro and thereby pulmonary vascular remodeling during chronic hypoxic exposure in vivo. Furthermore, by using RNA sequencing of pulmonary vessels at different time points after in vivo chronic hypoxic exposure of mice, we identified novel treatment targets during the process of reverse remodeling which are related to mitochondrial signaling in the early phase and matrix remodeling in the late phase of remodeling. Inhibition of one of the most prominent factors, the extracellular matrix secreted protein acidic and rich in cysteine (SPARC) glycoprotein, attenuated development of murine chronic hypoxia-induced PH.
We thus now aim to 1) decipher the molecular mechanism of Cox4i2-dependent redox alterations underlying HPV, 2) compare the role of the “oxygen-sensing” pericyte-like cell type in addition to PASMC for acute oxygen sensing, 3) investigate the relevance of decreased ROS release for development of chronic hypoxia-induced PH and 4) further delineate new therapeutic targets for reverse remodeling in novel animal models with persistent PH after re-exposure to normoxia. Using state-of-the-art technology (e.g. mass spectroscopy, RAMAN spectroscopy, single cell sequencing) we aim to identify the fundamental molecular principles of oxygen sensing and signal transduction underlying acute, sustained and chronic hypoxia-induced PH, and to establish novel treatment strategies to reverse PH.
