Oxidation of PKGIα mediates an endogenous adaptation to pulmonary hypertension

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

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

Chronic hypoxia causes pulmonary hypertension (PH), vascular remodeling, right ventricular (RV) hypertrophy, and cardiac failure. Protein kinase G Iα (PKGIα) is susceptible to oxidation, forming an interprotein 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 wild-type 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 before structural remodeling identified up-regulation of endothelial-to-mesenchymal transition pathways in the KI compared with 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 signaling.

Original languageEnglish
Pages (from-to)13016-13025
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number26
DOIs
Publication statusPublished - 2019

Keywords

  • Hypoxia
  • Oxidative stress
  • Protein kinase G
  • Pulmonary hypertension
  • Redox

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Oxidation of PKGIα mediates an endogenous adaptation to pulmonary hypertension'. Together they form a unique fingerprint.

Cite this