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JNK2 Regulates Vascular Remodeling in Pulmonary Hypertension
Author(s) -
Das Mita,
Zawada W. Michael,
West James,
Stenmark Kurt
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.774.5
Subject(s) - phosphorylation , kinase , hypoxia (environmental) , pathophysiology , pulmonary hypertension , extracellular matrix , gene isoform , extracellular , phosphatase , medicine , chemistry , endocrinology , pathology , microbiology and biotechnology , biology , biochemistry , organic chemistry , oxygen , gene
Structural alterations of pulmonary arterial (PA) wall are the key pathological features of pulmonary hypertension (PH). Although such vascular abnormalities correlate with heightened phosphorylation of c‐Jun N‐terminal kinases 1/2 (JNK1/2) in rat models of PH, contribution of each individual JNK isoform to the pathophysiology of PH is unknown. Hence, we hypothesized that activation of either one, or both JNK isoforms regulates PA wall thickening in PH. Comparing JNK1/2 activation in lungs of healthy individuals vs lungs of PH patients showed robust JNK1/2 phosphorylation (an index of JNK activation) accompanied by remarkable vascular thickening only in the disease‐affected lungs. In PH patients’ lungs, increased JNK1/2 phosphorylation paralleled marked reduction in MAP kinase phosphatase 1 (a key JNK dephosphorylator) expression. Association of JNK1/2 activation with vascular wall thickening was then confirmed in a well‐established neonatal calf model of hypoxia‐induced PH. To ascertain the role of each JNK isoform in PH pathophysiology, wild‐type (WT), JNK1 null (JNK1 −/− ), and JNK2 null (JNK2 −/− ) mice were exposed for six weeks to either normoxia (ambient air) for control or chronic hypoxia (10% O 2 ) to develop PH. Hypoxia stimulated an increase in JNK1/2 phosphorylation that associated with the development of PH like pathology i.e. excessive accumulation of extracellular matrix, small vessel (20–100 μm diameter) muscularization with medial wall thickening, and up‐regulation of small vessel density in WT mouse lungs. Similar to the hypoxia‐exposed WT lungs, increase in deposition of extracellular matrix and structural remodeling of the vascular wall were also detected in hypoxic JNK1 −/− lungs. In contrast, JNK2 −/− mice lacked such hypoxia‐induced up‐regulation of matrix accumulation as well as vascular abnormalities in the lung. However, right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH) were increased to a similar magnitude by hypoxia among all three genotypes. Our findings suggest that JNK2 regulates hypoxia‐induced PA structural thickening and that selectively modulating JNK2 actions might quell vascular abnormalities in PH. Support or Funding Information National Institutes of Health HL64917