Hypoxia activates Jun-N-terminal kinase, extracellular signal-regulated protein kinase, and p38 kinase in pulmonary arteries

Chronic alveolar hypoxia is the major cause of pulmonary hypertension. The cellular mechanisms involved in hypoxia-induced pulmonary arterial remodeli ng are still poorly understood. Mitogen-activated protein kinase (MAPK) is a key enzyme in the signaling pathway leading to cellular growth and prolif eration. The purpose of this investigation was to determine the roles that MAPKs, specifically jun-N-terminal kinase (JNK), extracellular signal-regul ated protein kinase (ERK), and p38 kinase, play in the hypoxia-induced pulm onary arterial remodeling. Rats were exposed to normobaric hypoxia (10% O-2 ) for 1, 3, 7, or 14 d. Hypoxia caused significant remodeling in the pulmon ary artery characterized by thickening of pulmonary arterial wall and incre ases in tissue mass and total RNA. JNK, ERK, and p38 kinase tyrosine phosph orylations and their activities were significantly increased by hypoxia. JN K activation peaked at Day 1 and ERK/p38 kinase activation peaked after 7 d of hypoxia. The results from immunohistochemistry show that hypoxia increa sed phospho-MAPK staining in both large and small intrapulmonary arteries. Hypoxia also upregulated vascular endothelial growth factor messenger RNA ( mRNA) and platelet-derived growth factor receptor mRNA levels in pulmonary artery with a time course correlated to the activation of ERK and p38 kinas e. The gene expressions of c-jun, c-fos, and egr-1, known as downstream eff ecters of MARK, were also investigated. Hypoxia upregulated egr-1 mRNA but downregulated c-jun and c-fos mRNAs. These data suggest that hypoxia-induce d activation of JNK is an early response to hypoxic stress and that activat ion of ERK and p38 kinase appears to be associated with hypoxia-induced pul monary arterial remodeling.