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Hypoxia Induces Non-Ligand–Dependent Activation of Mitogen-Activated Protein Kinases in Pulmonary Artery Adventitial Fibroblasts*: Role in Proliferation and Apoptosis FREE TO VIEW

Mita Das, PhD; Marla Moore, MD; Raphael Nemenoff, PhD; Kurt R. Stenmark, MD
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*From the Developmental Lung Biology Laboratory (Drs. Das, Moore, and Stenmark), and Division of Renal Medicine (Dr. Nemenoff), University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: Mita Das, PhD, Developmental Lung Biology Laboratory, University of Colorado Health Sciences Center, 4200 East Ninth Ave, Denver, CO 80262

Chest. 2001;120(1_suppl):S74. doi:10.1378/chest.120.1_suppl.S74
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Dramatic fibroproliferative changes in the adventitia of pulmonary arteries (PAs) have been observed in humans and animal models of chronic hypoxic pulmonary hypertension. We have shown that proliferation and apoptosis contribute to this remodeling response. We tested the hypothesis that hypoxia, in the absence of exogenous comitogens, acts directly on PA adventitial fibroblasts to induce proliferation and apoptosis and that the responses are dependent on differential activation of mitogen-activated protein (MAP) kinase family members. Hypoxia (3% O2) stimulated increases in DNA synthesis above normoxic levels in growth-arrested (5 days) PA fibroblasts. Simultaneously, a twofold increase in the apoptotic rate of fibroblasts was observed. The net result, however, was an increase in total cell number over 3 days of hypoxic exposure. Hypoxia, in the absence of exogenous mitogens, induced activation of extracellular signal-regulated kinase (ERK)-1/2, c-Jun NH2-terminal kinase (JNK)-1/2, and p38 MAP kinases. The increase in ERK activation occurred within 5 min of hypoxic exposure and was sustained for 60 min (ERK-1) and 24 h (ERK-2). Hypoxia induced an early (10 min) and very transient increase in JNK-1/2 activation. Hypoxia also activated p38 MAP kinase and, interestingly, the activation was biphasic (10 min and 24 h). PD98059 (an inhibitor of ERK), antisense oligonucleotide construct of JNK-1, and SB202190 (an antagonist of p38 kinase) all attenuated the hypoxia-induced proliferative responses of PA fibroblasts, suggesting that the ERK, JNK-1, and p38 MAP kinases might be involved in the hypoxic growth responses. In contrast, proliferation was augmented and apoptosis was reduced in the presence of JNK-2 antisense oligonucleotide constructs under hypoxic conditions, raising the possibility that JNK-2 may play an important role in hypoxia-induced apoptosis of fibroblasts. Blockade of the hypoxia-induced apoptotic responses in fibroblasts by SB202190 also suggested involvement of p38 MAP kinases in apoptosis. To determine the specific upstream activators of ERK and their role in proliferation, inhibitors of G-proteins and redox pathways were tested because of their purported involvement in ligand-independent proproliferative signaling. Both pertussis toxin and diphenyliodonium (an nicotinamide adenine dinucleotide phosphate oxidase inhibitor) attenuated hypoxia-induced proliferation, suggesting hypoxic activation of upstream Gi-coupled signaling pathways might occur in a ligand-independent manner. We conclude that adventitial remodeling during hypoxic pulmonary hypertension may result from a balance of proliferative and apoptotic responses that are mediated by non-ligand–dependent signaling through a complex network of MAP kinases.

Abbreviations: ERK = extracellular signal-regulated kinase; JNK = c-Jun NH2-terminal kinase; MAP = mitogen-activated protein; PA = pulmonary artery




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