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Abstract Pulmonary vascular medial hypertrophy due to proliferation of pulmonary artery smooth muscle cells (PASMC) greatly contributes to the increased pulmonary vascular resistance in pulmonary hypertension patients. A rise in cytosolic free Ca 2+ concentration (Ca 2+ cyt ) is an important stimulus for cell growth in PASMC. Resting Ca 2+ cyt , intracellularly stored Ca 2+ , capacitative Ca 2+ entry (CCE), and store-operated Ca 2+ currents ( I SOC ) are greater in proliferating human PASMC than in growth-arrested cells. Expression of TRP1, a transient receptor potential gene proposed to encode the channels responsible for CCE and I SOC , was also upregulated in proliferating PASMC. Our aim was to determine if inhibition of endogenous TRP1 gene expression affects I SOC and CCE and regulates cell proliferation in human PASMC. Cells were treated with an antisense oligonucleotide (AS, for 24 h) specifically designed to cleave TRP1 mRNA and then returned to normal growth medium for 40 h before the experiments. Then, mRNA and protein expression of TRP1 was downregulated, and amplitudes of I SOC and CCE elicited by passive depletion of Ca 2+ from the sarcoplasmic reticulum using cyclopiazonic acid were significantly reduced in the AS-treated PASMC compared with control. Furthermore, the rate of cell growth was decreased by 50% in AS-treated PASMC. These results indicate that TRP1 may encode a store-operated Ca 2+ channel that plays a critical role in PASMC proliferation by regulating CCE and intracellular Ca 2+ cyt . store-operated calcium channels transient receptor potential channel Footnotes ↵ * Michele Sweeney, Ying Yu, and Oleksandr Platoshyn contributed equally to this work. This work was supported by National Heart, Lung, and Blood Institute Grants HL-66012, HL-54043, and HL-64945 to J. X.-J. Yuan. J. X.-J. Yuan is an Established Investigator of the American Heart Association. Address for reprint requests and other correspondence: J. X.-J. Yuan, Div. of Pulmonary & Critical Care Medicine, UCSD Medical Center, MC 8382, 200 W. Arbor Dr., San Diego, CA 92103-8382 (E-mail: xiyuan@ucsd.edu ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. First published February 8, 2002;10.1152/ajplung.00412.2001 Copyright © 2002 the American Physiological Society
AJP - Lung Cellular and Molecular Physiology – The American Physiological Society
Published: Jul 1, 2002
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