Diminished sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) expression contributes to airway remodelling in bronchial asthama

Katharina Mahn, Stuart John Hirst, Sun Ying, Mark R Holt, Paul Lavender, Oluwaseun Ojo, Leonard Siew, D E Simcock, Clare G McVicker, V Kanabar, Vladimir Snetkov, B J O'Connor, C Karner, David J Cousins, Patricia Macedo, K Fan Chung, Christopher J Corrigan, Jeremy PT Ward, Tak H Lee

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Abstract

Phenotypic modulation of airway smooth muscle (ASM) is an important feature of airway remodeling in asthma that is characterized by enhanced proliferation and secretion of pro-inflammatory chemokines. These activities are regulated by the concentration of free Ca2plus in the cytosol ([Ca2plus]i). A rise in [Ca2plus]i is normalized by rapid reuptake of Ca2plus into sarcoplasmic reticulum (SR) stores by the sarco/endoplasmic reticulum Ca2plus (SERCA) pump. We examined whether increased proliferative and secretory responses of ASM from asthmatics result from reduced SERCA expression. ASM cells were cultured from subjects with and without asthma. SERCA expression was evaluated by western blot, immunohistochemistry and real-time PCR. Changes in [Ca2plus]i, cell spreading, cellular proliferation, and eotaxin-1 release were measured. Compared with control cells from healthy subjects, SERCA2 mRNA and protein expression was reduced in ASM cells from subjects with moderately severe asthma. SERCA2 expression was similarly reduced in ASM in vivo in subjects with moderate/severe asthma. Rises in [Ca2plus]i following cell surface receptor-induced SR activation, or inhibition of SERCA-mediated Ca2plus re-uptake, were attenuated in ASM cells from asthmatics. Likewise, the return to baseline of [Ca]i after stimulation by bradykinin was delayed by approximately 50 in ASM cells from asthmatics. siRNA-mediated knockdown of SERCA2 in ASM from healthy subjects increased cell spreading, eotaxin-1 release and proliferation. Our findings implicate a deficiency in SERCA2 in ASM in asthma that contributes to its secretory and hyperproliferative phenotype in asthma, and which may play a key role in mechanisms of airway remodeling.
Original languageEnglish
Pages (from-to)10775 - 10780
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number26
Publication statusPublished - 2009

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