Abstract 11483: Prevention of Myocardial Ischemia-Reperfusion Injury in Cardiac-Specific SOCS3 Knockout Mice by Inhibiting Pro-Inflammatory Pathways
BACKGROUND: Although JAK-STAT signaling activating cytokines have been shown to prevent myocardial ischemia-reperfusion (IR) injury, little is known about the negative regulation of the JAK-STAT pathway in the development of IR injury. We previously showed that suppressor of cytokine signaling 3 (SOCS3) is an intrinsic negative regulator of cytokine-induced STAT3 activation. In this study, we investigated the role of myocardial SOCS3 during IR injury.
METHODS AND RESULTS: Myocardial IR injury was induced by ligation (1 h) of the left anterior descending coronary artery, followed by different reperfusion time in cardiac-specific SOCS3 knockout mice (SOCS3-CKO) and controls. Evans blue and 1% TTC staining after a 24 h reperfusion showed a 33% reduction in myocardial infarct size in SOCS3-CKO 24-hr compared to controls (p<0.05). TUNEL staining revealed that, after 6 h of reperfusion, apoptotic cells were significantly decreased in SOCS3-CKO compared to controls (p<0.05). STAT3 phosphorylation was faint at 1 h after ischemia, marked at 20 min after reperfusion, and suppressed at 3 h after reperfusion; this transient activation of STAT3 was closely correlated with the induction of SOCS3 in controls. In contrast, STAT3, AKT, and ERK1/2 phosphorylation after reperfusion was significantly greater in SOCS3-CKO than in controls (p<0.05). Thus, myocardial IR injury was prevented in SOCS3-CKO by augmenting multiple cardioprotective signaling pathways. To investigate the mechanism underlying the prevention of myocardial IR injury in SOCS3-CKO, we conducted a genechip analysis with an Agilent, whole mouse genome, oligo DNA microarray. We divided mice into four groups, including controls with a sham operation, controls with an IR injury, SOCS3-CKO with a sham operation, and SOCS3-CKO with an IR injury (n=5, in each group). Interestingly, we found that large numbers of genes involved in pro-inflammatory pathways were significantly down-regulated in SOCS3-CKO compared to controls at 3 h after reperfusion. These genes included IL-1, IL-6, TNF-α, chemokine (C-C motif) ligands, and chemokine (C-X-C motif) ligands.
CONCLUSION: These results suggested that myocardial IR injury may have been prevented in SOCS3-CKO by inhibition of the pro-inflammatory pathways.
- © 2011 by American Heart Association, Inc.