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Oxidation of PKGIα mediates an endogenous adaptation to pulmonary hypertension

Research output: Contribution to journalArticlepeer-review

Olena Rudyk, Alice Rowan, Oleksandra Prysyazhna, Susanne Krasemann, Kristin Hartmann, Min Zhang, Ajay Manmohan Shah, Clemens Ruppert, Astrid Weiss, Ralph Theo Schermuly, Tomoaki Ida, Takaaki Akaike, Lan Zhao, Philip Eaton

Original languageEnglish
Pages (from-to)13016-13025
Number of pages10
JournalPNAS
Volume116
Issue number26
Early online date11 Jun 2019
DOIs
Accepted/In press21 May 2019
E-pub ahead of print11 Jun 2019
Published25 Jun 2019

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Abstract

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.

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