Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCA334

Poster Communications

Hypoxic stabilized p22phox modulates vascularization in vitro and in vivo and promotes pulmonary hypertension

A. Petry1, B. Trautz1, D. Kracun1, Z. Zhang1, M. Weitnauer1, A. Görlach1

1. Experimental and Molecular Pediatric Cardiology, German Heart Center Munich, Munich, Germany.


Background: Hypoxia and reactive oxygen species (ROS) have been shown to play a role in the pathogenesis of pulmonary hypertension, a potentially fatal disorder characterized by pulmonary vascular remodeling, elevated pulmonary arterial pressure and right ventricular hypertrophy. The multiprotein enzymes of the NADPH oxidase family are an important source of cardiovascular ROS. However, how they are linked in the context of hypoxia-induced pulmonary hypertension is not completely understood. Aims: We therefore investigated the role of p22phox, which is required for ROS production of the majority of NADPH oxidases, in the response to hypoxia in vitro and in vivo. Results: We found that hypoxia decreased ubiquitinylation and proteasomal degradation of p22phox which was dependent on prolyl hydroxylases and the E3 ubiquitin ligase pVHL, and resulted in p22phox stabilization and accumulation. Hypoxic induction of p22phox contributed to ROS generation after reoxygenation, and promoted endothelial cell proliferation, migration and angiogenesis under hypoxia. On the other hand, in mice harboring a point mutation (Y121H) in the p22phox gene which resulted in decreased p22phox stability and subsequent loss of this protein, sprouting of pulmonary vessels and in vivo angiogenesis were reduced. Mechanistically, p22phox promoted HIF activity and stabilization of HIF1α, the major cellular regulator of hypoxia adaptation. This response was mediated by reduction of ascorbate and Fe(II) levels which are required for activity of prolyl hydroxylases. Increased levels of p22phox , HIF1α and ATF4 -a mediator of the integrated stress response -were also detected in lungs and hearts from wildtype mice with hypoxia-induced pulmonary hypertension. On the contrary, p22phox deficient mice were protected against the development of hypoxia-induced pulmonary hypertension. Concomitantly, HIF1α, and ATF4-levels were decreased, while the levels of miR-140, a tumor suppressor miRNA which protects against pulmonary hypertension, were increased in lungs and hearts from hypoxic p22phox-deficient mice. Conclusion: These data identify p22phox as important regulator of the hypoxia response in vitro and in vivo Inhibition of p22phox-dependent NADPH oxidases might be a promising therapeutic strategy against pulmonary hypertension induced by hypoxia and possibly other conditions.

Where applicable, experiments conform with Society ethical requirements