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Na + /H + exchange (NHE) inhibitors prevent pulmonary arterial smooth muscle cell (PASMC) proliferation induced by hypoxia
Author(s) -
Undem Clark,
Luke Trevor,
Shimoda Larissa A
Publication year - 2007
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.21.6.a1436-c
Subject(s) - hypoxia (environmental) , cell growth , in vivo , pulmonary hypertension , hypoxic pulmonary vasoconstriction , intracellular ph , amiloride , chemistry , medicine , endocrinology , intracellular , biology , biochemistry , oxygen , microbiology and biotechnology , sodium , organic chemistry
Prolonged hypoxia, as occurs in many lung diseases, can result in the development of pulmonary hypertension. One factor that contributes to the development of this condition is increased muscularity of the pulmonary vasculature, mediated, in part, by PASMC proliferation. Previous studies demonstrated that PASMC proliferation in response to growth factors required increased intracellular pH (pH i ) due to activation of NHE. Moreover, in chronically hypoxic rats, PASMCs exhibited elevated NHE activity and pH i whereas NHE inhibitors attenuated development of pulmonary vascular remodeling, suggesting a prominent role for NHE in regulating hypoxia‐induced PASMC growth responses. In this study, we determined whether PASMCs exhibited increased proliferation in response to in vivo and ex vivo hypoxia and the role of NHE in this response. PASMCs were isolated from normoxic and chronically hypoxic (3 wks, 10% O 2 ) rats, and cultured for 24–48 hours to allow recovery from the digestion process. Cells were washed to remove non‐adherent PASMCs, trypsinized and counted. Equal numbers of cells were placed in 25 mm Petri dishes for cell counts or into 96 well plates for measurement of proliferation via ELISA and cultured for 72 hours with or without ethylisopropyl amiloride (EIPA), a NHE inhibitor. Cells from hypoxic rats exhibited greater proliferation compared to cells from normoxic animals, as did PASMCs from normoxic animals cultured under hypoxic conditions (1% O 2 ). EIPA markedly reduced proliferation in PASMCs from all groups. Our findings indicate that during hypoxia, activation of NHE contributes to proliferation in PASMCs. Funded by: HL67191, HL73589