AffiliationUniv Arizona, Coll Med Phoenix, Dept Internal Med
MetadataShow full item record
PublisherSAGE PUBLICATIONS INC
CitationDas, M., Zawada, W. M., West, J. D., & Stenmark, K. R. EXPRESS: JNK2 Regulates Vascular Remodeling in Pulmonary Hypertension. Pulmonary Circulation 2018; 8(3) 1–13. DOI: 10.1177/2045894018778156
Rights© The Author(s) 2018. Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License.
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AbstractPulmonary arterial (PA) wall modifications are key pathological features of pulmonary hypertension (PH). Although such abnormalities correlate with heightened phosphorylation of c-Jun N-terminal kinases 1/2 (JNK1/2) in a rat model of PH, the contribution of specific JNK isoforms to the pathophysiology of PH is unknown. Hence, we hypothesized that activation of either one, or both JNK isoforms regulates PA remodeling in PH. We detected increased JNK1/2 phosphorylation in the thickened vessels of PH patients' lungs compared to that in lungs of healthy individuals. JNK1/2 phosphorylation paralleled a marked reduction in MAP kinase phosphatase 1 JNK dephosphorylator) expression in patients' lungs. Association of JNK1/2 activation with vascular modification was confirmed in the calf model of severe hypoxia-induced PH. To ascertain the role of each JNK isoform in pathophysiology of PH, wild-type (WT), JNK1 null (JKN1(-/-)), and JNK2 null (JNK2(-/)(-)) mice were exposed to chronic hypoxia (10% O-2 for six weeks) to develop PH. In hypoxic WT lungs, an increase in JNK1/2 phosphorylation was associated with PH-like pathology. Hallmarks of PH pathophysiology, i.e. excessive accumulation of extracellular matrix and vessel muscularization with medial wall thickening, was also detected in hypoxic JNK1(-/-) lungs, but not in hypoxia-exposed JNK2(-/-) lungs. However, hypoxia-induced increases in right ventricular systolic pressure (RVSP) and in right ventricular hypertrophy (RVH) were similar in all three genotypes. Our findings suggest that JNK2 participates in PA remodeling (but likely not in vasoconstriction) in murine hypoxic PH and that modulating JNK2 actions might quell vascular abnormalities and limit the course of PH.
Note12 month embargo; published online: 3 July 2018
VersionFinal published version
SponsorsNational Heart, Lung and Blood Institute [HL64917 MD]; A. T. Still University startup funds
Except where otherwise noted, this item's license is described as © The Author(s) 2018. Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License.
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