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Aberrant Signal Transduction In Pulmonary Hypertension*

Kirk B. Lane, PhD; Thomas R. Blackwell, BS; James Runo, MD; Lisa Wheeler, BS; John A. Phillips, III, MD; James E. Loyd, MD, FCCP
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*From the Divisions of Allergy, Pulmonary, and Critical Care Medicine (Drs. Lane, Runo, Loyd and Mr. Blackwell and Ms. Wheeler) and Medical Genetics (Dr. Phillips), Vanderbilt University School of Medicine, Nashville, TN.

Correspondence to: James E. Loyd, MD, FCCP, Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, TN; e-mail: jim.loyd@vanderbiltt.edu



Chest. 2005;128(6_suppl):564S-565S. doi:10.1378/chest.128.6_suppl.564S-a
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Primary pulmonary hypertension (PPH) is a lethal disorder that usually comes to medical attention when pulmonary vascular occlusion is advanced. Six percent of the PPH cases in the 1987 National Institutes of Health Registry cluster in families. Heterogeneous mutations in the gene coding for bone morphogenic protein receptor 2 (BMPR2) are responsible for most of the familial cases. Approximately 40 different mutations have a common phenotype, PPH; therefore, we hypothesized that these diverse mutations in BMPR2 create a common molecular defect in one of the downstream pathways linked to this receptor. By immunohistochemistry, we show that the extracellular receptor kinase (ERK) branch of the mitogen-activated protein kinase signaling pathway is aberrant in vessels of patients with PPH. We further demonstrate by Western blot analysis that this increase in basal ERK activation is present in primary pulmonary vascular smooth-muscle cells cultured from several affected PPH patients with dissimilar BMPR2 mutations. The alteration in ERK signaling was also recreated in cell lines engineered to express mutations responsible for PPH expression. Using both primary cells from PPH patients and cell lines created to express BMPR2 disease alleles, we provide evidence that the altered ERK signaling is a direct effect of mutant BMPR2 proteins. Cells expressing the BMPR2 alleles associated with PPH alter ERK signaling to increase cell growth, which corresponds with the cellular phenotype seen in PPH vessels. This growth is not the result of decreased apoptosis. These findings are similar in primary smooth-muscle cells obtained from PPH patients. These results suggest that the primary defect in PPH is altered ERK signaling resulting in a promitotic environment. Our results suggest that interventions that inhibit cellular growth could be efficacious in treatment of PPH. 1286

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