TY - JOUR
T1 - PAR-2 activation at the time of reperfusion salvages myocardium via an ERK1/2 pathway in in vivo rat hearts
AU - Jiang, Rong
AU - Zatta, Amanda
AU - Kin, Hajime
AU - Wang, Ningping
AU - Reeves, James
AU - Mykytenko, James
AU - Deneve, Jeremiah
AU - Zhao, Zhi-Qing
AU - Guyton, Robert
AU - Vinten-Johansen, Jakob
PY - 2007
Y1 - 2007
N2 - PAR-2 activation
at the time of reperfusion salvages myocardium via an ERK1/2 pathway in
in vivo rat hearts. Am J Physiol Heart Circ Physiol 293: H2845a??H2852,
2007. First published August 24, 2007; doi:10.1152/ajpheart.00209.2007.a??
Protease-activated receptor-2 (PAR-2) may have proinflammatory effects
in some tissues and protective effects in other tissues. The role
of PAR-2 in in vivo myocardial ischemia-reperfusion has not yet been
determined. This study tested the hypothesis that PAR-2 activation
with the PAR-2 agonist peptide SLIGRL (PAR-2 AP) reduces myocardial
infarct size when given at reperfusion in vivo, and this
cardioprotection involves the ERK1/2 pathway. Anesthetized rats
were randomly assigned to the following groups with 30 min of
regional ischemia and 3 h reperfusion: 1) control with saline; 2) vehicle
(DMSO); 3) PAR-2 AP, 1 mg/kg given intravenously 5 min
before reperfusion; 4) scrambled peptide (SP), 1 mg/kg; 5) the
ERK1/2 inhibitor PD-98059 (PD), 0.3 mg/kg given 10 min before
reperfusion; 6) the phosphatidylinositol 3-kinase inhibitor LY-294002
(LY), 0.3 mg/kg given 10 min before reperfusion; 7) PD PAR-2
AP, 0.3 mg/kg PD given 5 min before PAR-2 AP; 8) LY PAR-2
AP, 0.3 mg/kg LY given 5 min before PAR-2 AP; 9) chelerythrine
(Chel) alone, 5 mg/kg given 10 min before reperfusion; and
10) Chel PAR-2 AP, Chel was given 5 min before PAR-2 AP (10
min before reperfusion). Activation of ERK1/2, ERK5, Akt, and the
downstream targets of ERK1/2 [P90 RSK and bcl-xl/bcl-2-associated
death promoter (BAD)] was determined by Western blot analysis in
separate experiments. PAR-2 AP significantly reduced infarct size
compared with control (36 2 vs. 53 1 , P 0.05), and SP had
no effect on infarct size (53 3 ). PAR-2 AP significantly increased
phosphorylation of ERK1/2, p90RSK, and BAD but not Akt or ERK5.
Accordingly, the infarct-size sparing effect of PAR-2 AP was abolished
by PD (PAR-2 AP, 36 2 vs. PD PAR-2 AP, 50 1 ;
P 0.05) and by Chel (Chel PAR-2 AP, 58 2 ) but not by LY
(PAR-2 AP, 36 2 vs. LY PAR-2 AP, 38 3 ; P 0.05).
Therefore, PAR-2 activation is cardioprotective in the in vivo rat heart
ischemia-reperfusion model, and this protection involves the ERK1/2
pathway and PKC.
AB - PAR-2 activation
at the time of reperfusion salvages myocardium via an ERK1/2 pathway in
in vivo rat hearts. Am J Physiol Heart Circ Physiol 293: H2845a??H2852,
2007. First published August 24, 2007; doi:10.1152/ajpheart.00209.2007.a??
Protease-activated receptor-2 (PAR-2) may have proinflammatory effects
in some tissues and protective effects in other tissues. The role
of PAR-2 in in vivo myocardial ischemia-reperfusion has not yet been
determined. This study tested the hypothesis that PAR-2 activation
with the PAR-2 agonist peptide SLIGRL (PAR-2 AP) reduces myocardial
infarct size when given at reperfusion in vivo, and this
cardioprotection involves the ERK1/2 pathway. Anesthetized rats
were randomly assigned to the following groups with 30 min of
regional ischemia and 3 h reperfusion: 1) control with saline; 2) vehicle
(DMSO); 3) PAR-2 AP, 1 mg/kg given intravenously 5 min
before reperfusion; 4) scrambled peptide (SP), 1 mg/kg; 5) the
ERK1/2 inhibitor PD-98059 (PD), 0.3 mg/kg given 10 min before
reperfusion; 6) the phosphatidylinositol 3-kinase inhibitor LY-294002
(LY), 0.3 mg/kg given 10 min before reperfusion; 7) PD PAR-2
AP, 0.3 mg/kg PD given 5 min before PAR-2 AP; 8) LY PAR-2
AP, 0.3 mg/kg LY given 5 min before PAR-2 AP; 9) chelerythrine
(Chel) alone, 5 mg/kg given 10 min before reperfusion; and
10) Chel PAR-2 AP, Chel was given 5 min before PAR-2 AP (10
min before reperfusion). Activation of ERK1/2, ERK5, Akt, and the
downstream targets of ERK1/2 [P90 RSK and bcl-xl/bcl-2-associated
death promoter (BAD)] was determined by Western blot analysis in
separate experiments. PAR-2 AP significantly reduced infarct size
compared with control (36 2 vs. 53 1 , P 0.05), and SP had
no effect on infarct size (53 3 ). PAR-2 AP significantly increased
phosphorylation of ERK1/2, p90RSK, and BAD but not Akt or ERK5.
Accordingly, the infarct-size sparing effect of PAR-2 AP was abolished
by PD (PAR-2 AP, 36 2 vs. PD PAR-2 AP, 50 1 ;
P 0.05) and by Chel (Chel PAR-2 AP, 58 2 ) but not by LY
(PAR-2 AP, 36 2 vs. LY PAR-2 AP, 38 3 ; P 0.05).
Therefore, PAR-2 activation is cardioprotective in the in vivo rat heart
ischemia-reperfusion model, and this protection involves the ERK1/2
pathway and PKC.
UR - http://PAR-2 activation at the time of reperfusion salvages myocardium via an ERK1/2 pathway in vivo rat hearts
M3 - Article
SN - 0363-6135
VL - 293
SP - 2845
EP - 2852
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 5
ER -