Hypoxia Activates Jun-N-Terminal Kinase, Extracellular Signal–Regulated Protein Kinase, and p38 Kinase in Pulmonary Arteries

Abstract

Chronic alveolar hypoxia is the major cause of pulmonary hypertension. The cellular mechanisms involved in hypoxia- induced pulmonary arterial remodeling are still poorly understood. Mitogen-activated protein kinase (MAPK) is a key enzyme in the signaling pathway leading to cellular growth and proliferation. The purpose of this investigation was to determine the roles that MAPKs, specifically Jun-N-terminal kinase (JNK), extracellular signal-regulated protein kinase (ERK), and p38 kinase, play in the hypoxia-induced pulmonary arterial remodeling. Rats were exposed to normobaric hypoxia (10% O(2)) for 1, 3, 7, or 14 d. Hypoxia caused significant remodeling in the pulmonary artery characterized by thickening of pulmonary arterial wall and increases in tissue mass and total RNA. JNK, ERK, and p38 kinase tyrosine phosphorylations and their activities were significantly increased by hypoxia. JNK activation peaked at Day 1 and ERK/p38 kinase activation peaked after 7 d of hypoxia. The results from immunohistochemistry show that hypoxia increased 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 kinase. The gene expressions of c-jun, c-fos, and egr-1, known as downstream effectors of MAPK, were also investigated. Hypoxia upregulated egr-1 mRNA but downregulated c-jun and c-fos mRNAs. These data suggest that hypoxia-induced activation of JNK is an early response to hypoxic stress and that activation of ERK and p38 kinase appears to be associated with hypoxia-induced pulmonary arterial remodeling.

Schistosomiasis-Induced Experimental Pulmonary Hypertension

“…We also observed elevations in p42/44 MAPK in IL-13R␣1 Ϫ/Ϫ and IL-13R␣2 Ϫ/Ϫ mice compared with wild-type mice, independent of S. mansoni infection, and thus the contribution of p42/44 MAPK to PH in this model is unclear. Indeed, prior studies have shown increased expression of p42/44 MAPK in rats exposed to chronic hypoxia, 49 but which may not be necessary for the hypertensive response. 50 Abnormal TGF-␤ family signaling has been linked to human and experimental PAH.…”

Induction of hypervascularity without leakage or inflammation in transgenic mice overexpressing hypoxia-inducible factor-1α

“…For instance, both flt-1 and iNOS are known HIF-1␣ target genes in endothelial cells, yet our preliminary data (not shown) suggest that these genes are not up-regulated in the K14-HIF-1␣⌬ODD transgenic mice. Moreover, hypoxia itself may induce additional cytokine expression or recruit other master regulatory transcription factors within specific cell types, such as Egr-1 up-regulation in hypoxic endothelium (Jin et al 2000), that may mediate blood vessel permeability alone or combined with HIF-1␣ stabilization. Additional modulators of permeability may also exist in vessels in hypoxic wounds and tumors, which are known to be leaky (for review, see Carmeliet and Jain 2000).…”

Hydrogen Peroxide-Induced Extracellular Signal-Regulated Kinase Activation in Cultured Feline Ileal Smooth Muscle Cells

“…It has recently been reported that H 2 O 2 stimulated tyrosine kinase activity and caused receptor tyrosine phosphorylation, suggesting that H 2 O 2 -induced mitogenic response is, in part, mediated through platelet-derived growth factor receptor in aortic smooth muscle cells (Jin et al, 2000). Among two classic tyrosine kinases, receptor and nonreceptor tyrosine kinases, receptor tyrosine kinases virtually are the growth factor receptors located in the inner side of the cytoplasmic membrane and subjected to dimerization and autophosphorylation upon activation.…”