Mucosal inflammation results in altered contractility, calcium mobilization, and CaMKII signaling in colon smooth muscles.
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Authors
Qureshi, Sadeea
Issue Date
2011
Type
Dissertation
Language
Keywords
calcium waves , CaM kinase II , colonic smooth muscle , DSS-colitis , phospholamban , SR Calcium ATPase
Alternative Title
Abstract
Ulcerative colitis is an inflammatory bowel disease that causes malnourishment,
weight loss, and bloody diarrhea in patients. Inflammation of the gut is associated with
colonic dysmotility that changes mucosal functions and contributes to increased urgency
and frequency of defecation in ulcerative colitis patients. Since the etiology of IBD is
unclear and with incidence on the rise, much research in IBD has focused on
understanding the underlying pathophysiology to uncover novel, specific therapeutic
targets to accommodate the large population affected.
Altered colonic smooth muscle calcium mobilization has been implicated in the
development of colonic dysmotility in inflammatory bowel disease. Alterations in key
Ca2+-transporter proteins, including the sarcoplasmic reticulum Ca2+-ATPase (SERCA2),
have been reported for animal models of colitis. Changes in fura-2 Ca2+ signals that
indicate reduced intracellular Ca2+ stores have been observed in patients with ulcerative
colitis and in animal models of the disease. Therefore, the overall goal of this
dissertation was to investigate the mechanisms by which disrupted intracellular Ca2+
signals contributes to the impaired contractility of colonic circular smooth muscles.
Acute colitis was induced in male C57Bl/6 mice with dextran sulfate sodium
(DSS) in the drinking water. Proximal and distal colon smooth muscles from non-treated
controls and the first five days after DSS treatment were compared. Mechanical and
electrical activities of colonic smooth muscles were studied in the presence of agonists
and other drugs. Intracellular calcium waves and activity of the Ca2+/calmodulindependent protein kinase II (CaMKII) activity were explored. Protein expression of
ii
SERCA2, phospholamban (PLB), and !CaMKII was also examined in the DSS murine
model.
Spontaneous and agonist-evoked contractions of circular smooth muscle strips
from dextran sulfate sodium-treated mice were reduced compared to controls. Control
levels of contractile activity were not restored with tetrodotoxin. SERCA2 and PLB
expression was reduced in colonic smooth muscles from DSS-colitis mice. Intracellular
Ca2+ waves were altered in DSS-colitis smooth muscle cells in the presence of caffeine.
Expression of !CaMKII was increased in distal colon smooth muscle cells, but remained
unchanged in the proximal colon from DSS-colitis mice. In addition, total and
autonomous CaMKII activity was increased in colonic smooth muscles in DSS-colitis. In
distal colon smooth muscles, cytosolic levels of HDAC4 were increased and I"B# levels
were decreased in DSS-colitis.
The results in this dissertation suggest that disruptions in intracellular Ca2+
mobilization due to down-regulation of SERCA2 and PLB expression lead to increased
CaMKII activity and cytosolic HDAC4 that may contribute to the dysmotility of colonic
smooth muscles in colitis by enhancing NF-"B activity. In addition, CaMKII can signal
to other downstream targets that may interfere with smooth muscle cell function via gene
transcription or ion channel activation/deactivation, thus contributing to dysmotility. The
findings in this dissertation demonstrate a link between smooth muscle Ca2+ physiology
and inflammatory cytokine signaling and provide novel information to the underlying
pathogenesis of colonic dysmotility in ulcerative colitis.
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