| First Author | Rudyk O | Year | 2019 |
| Journal | Proc Natl Acad Sci U S A | Volume | 116 |
| Issue | 26 | Pages | 13016-13025 |
| PubMed ID | 31186362 | Mgi Jnum | J:277410 |
| Mgi Id | MGI:6316075 | Doi | 10.1073/pnas.1904064116 |
| Citation | Rudyk O, et al. (2019) Oxidation of PKGIalpha mediates an endogenous adaptation to pulmonary hypertension. Proc Natl Acad Sci U S A 116(26):13016-13025 |
| abstractText | Chronic hypoxia causes pulmonary hypertension (PH), vascular remodeling, right ventricular (RV) hypertrophy, and cardiac failure. Protein kinase G Ialpha (PKGIalpha) is susceptible to oxidation, forming an interprotein disulfide homodimer associated with kinase targeting involved in vasodilation. Here we report increased disulfide PKGIalpha 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 gamma-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 PKGIalpha observed. Inhibiting cystathionine gamma-lyase resulted in decreased hypoxia-induced disulfide PKGIalpha and more severe PH phenotype in wild-type mice, but not in Cys42Ser PKGIalpha knock-in (KI) mice that are resistant to oxidation. In addition, KI mice also developed potentiated PH during hypoxia alone. Thus, oxidation of PKGIalpha 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 PKGIalpha is an intrinsic adaptive mechanism that attenuates PH progression not only by promoting vasodilation but also by limiting maladaptive growth and fibrosis signaling. |
