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The spleen contributes importantly to myocardial infarct exacerbation during
post-ischemic reperfusion in mice via signaling between cardiac HMGB1 and splenic
RAGE
#MMPMID27645145
Tian Y
; Pan D
; Chordia MD
; French BA
; Kron IL
; Yang Z
Basic Res Cardiol
2016[Nov]; 111
(6
): 62
PMID27645145
show ga
The spleen plays a critical role in post-infarct myocardial remodeling. However,
the role of the spleen in exacerbating myocardial infarction (MI) during acute
ischemia/reperfusion (I/R) injury is unknown. The present study tests the
hypothesis that splenic leukocytes are activated by substances released from
ischemic myocardium to subsequently exacerbate myocardial injury during
reperfusion. The left coronary artery in C57BL/6 mice underwent various durations
of occlusion followed by 60 min of reperfusion (denoted as min/min of I/R) with
or without splenectomy prior to I/R injury. Splenectomy significantly decreased
myocardial infarct size (IS) in 40'/60' and 50'/60' groups (p < 0.05); however,
it had no effect on IS in 10'/60', 20'/60' and 30'/60' groups (p = NS). In the
20'/60' group, infusion of 40-min ischemic heart homogenate (40-IHH) upon
reperfusion increased IS by >threefold versus infusion of 10-IHH (p < 0.05).
Splenectomy abolished the infarct-exacerbating effect of 40-IHH, which was
restored by splenic leukocyte adoptive transfer (SPAT). Furthermore, depletion of
HMGB1 in the 40-IHH group abolished its infarct-exacerbating effect (p < 0.05),
and 40-IHH failed to increase IS in both RAGE(-/-) mice and splenectomized
wild-type mice with SPAT from RAGE(-/-) mice. The injection of 40-IHH
significantly increased formyl peptide receptor 1 (FPR1) expression in sham
spleens when compared to 10-IHH-treated sham and control mice. cFLFLF, a specific
FPR1 antagonist, reduced myocardial neutrophil infiltration and abrogated the
infarct-exacerbating effect of 40-IHH during reperfusion. A cardio
(HMGB1)-splenic (RAGE receptor) signaling axis exists and contributes to
myocardial infarct exacerbation during reperfusion after prolonged ischemic
insults by activating splenic leukocytes. The FPR1 is a potential therapeutic
target for inhibiting the cardio-splenic axis that augments infarct size during
post-ischemic reperfusion.
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