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 language | English |
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Pages (from-to) | 10775 - 10780 |
Number of pages | 6 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 106 |
Issue number | 26 |
Publication status | Published - 2009 |