Abstract 2947: Cardiac-Specific Deletion of SOCS3 Prevented Myocardial Apoptosis After Acute Myocardial Infarction Through Inhibiting Mitochondrial Damage
Background: Cytokines that activate JAK-STAT pathway have been shown to prevent the myocardial apoptosis after acute myocardial infarction (AMI). However, underlying mechanism by which JAK-STAT pathway prevents myocardial apoptosis after AMI is not fully understood. We have shown that suppressor of cytokine signaling 3 (SOCS3) is an intrinsic negative regulator of cytokine-induced STAT3 signaling. We determined whether STAT3 signaling and SOCS3 would play a role in myocardial apoptosis after AMI.
Methods and Results: First, to investigate the role of STAT3 signaling and SOCS3 in myocardial apoptosis after AMI, we generated cardiac-specific SOCS3 knockout mice (SOCS3-KO). We found that smaller infarct size, less left ventricular end-diastolic dimension (LVEDD), improved ejection fraction (EF) in SOCS3-KO compared to WT (infarct size, 36.9±3.5% vs. 57.5±2.3%, p<0.01; LVEDD, 4.4±0.2mm vs. 5.0±0.5mm, p<0.01; EF, 43.5±5.2% vs. 21.3±7.5%, p<0.01). The duration and intensity of STAT3 phosphorylation was greater in SOCS3-KO than WT.SOCS3-KO showed greater survival rate than WT after AMI (p<0.01). Next, we evaluated the apoptosis by TUNEL staining and western blot for cleaved-caspase-3, Bad, Bax and Bcl-xL after AMI. The number of TUNEL-positive cells (27.8±2.4% vs. 46.4±3.5%, p<0.01) and the expression of cleaved-caspase-3, Bad and Bax after AMI were significantly less in SOCS3-KO. On the other hand, the expression of Bcl-xL was much greater in SOCS3-KO, suggesting that myocardial apoptosis after AMI may be prevented via inhibiting mitochondrial apoptotic signaling pathway in SOCS3-KO. Therefore, we examined mitochondrial damage by western blot cytochrome c (Cyto-c) oxidase (COX) and release of Cyto-c from mitochondria to cytosol after AMI. The expression of COX II in mitochondria was greater and Cyto-c release in cytosol was less in SOCS3-KO than the WT. Furthermore, we found that expression of mitochondrial transcription factor A (TFAM), which is essential for mtDNA transcription and replication, was much greater in SOCS3-CKO after AMI.
Conclusion: These results suggest that the deletion of SOCS3 in cardiomyocytes may prevent the myocardial apoptosis after AMI via augmenting the STAT3 signaling and inhibiting mitochondrial damage.