Oxidation of PKGIα mediates an endogenous adaptation to pulmonary hypertension

Chronic hypoxia causes pulmonary hypertension (PH), vascular remodelling, right ventricular (RV) hypertrophy and cardiac failure. Protein kinase G Iα (PKGIα) is susceptible to oxidation, forming an inter-protein disulfide homodimer associated with kinase targeting involved in vasodilation. Here we report increased disulfide-PKGIα in pulmonary arteries from mice with hypoxic PH or lungs from patients with pulmonary arterial hypertension. This oxidation is likely caused by oxidants derived from NADPH oxidase-4, superoxide dismutase 3 and cystathionine γ-lyase, enzymes that were concomitantly increased in these samples. Indeed, products that may arise from these enzymes, including hydrogen peroxide, glutathione disulfide and protein-bound persulfides, were increased in the plasma of hypoxic mice. Furthermore, low molecular-weight hydropersulfides, which can serve as ‘superreductants’ were attenuated in hypoxic tissues, consistent with systemic oxidative stress and the oxidation of PKGIα observed. Inhibiting cystathionine γ-lyase resulted in decreased hypoxia-induced disulfide-PKGIα and more severe PH phenotype in wildtype mice, but not in Cys42Ser PKGIα knock-in (KI) mice that are resistant to oxidation. In addition, KI mice also developed potentiated PH during hypoxia alone. Thus, oxidation of PKGIα is an adaptive mechanism that limits PH, a concept further supported by polysulfide treatment abrogating hypoxia-induced RV hypertrophy in wild-type, but not in the KI mice. Unbiased transcriptomic analysis of hypoxic lungs prior to structural remodelling, identified upregulation of endothelial-to-mesenchymal transition pathways in the KI compared to wild-type mice. Thus, disulfide-PKGIα is an intrinsic adaptive mechanism that attenuates PH progression not only by promoting vasodilation, but also by limiting maladaptive growth and fibrosis signalling.