Abstract 3256: Cardiac-specific Deletion of SOCS3 Improved Lipopolysaccharide-Induced Cardiac Dysfunction via Mitochondria Stabilization
Background: Mechanisms for septic cardiac dysfunction is unknown. Lypopolysaccharide (LPS)-induced left ventricular (LV) dysfunction is a model of septic cardiac dysfunction. STAT3 signaling in the heart promotes cardiomyocyte survival during LPS-induced LV dysfunction. We have shown that suppressor of cytokine signaling 3 (SOCS3) is an intrinsic negative regulator of gp130 cytokine-induced STAT3 signaling. Here, we determined whether STAT3 signaling and SOCS3 would play a role in LPS-induced LV dysfunction.
Methods and Results: We examined the activation of STAT3 and inductions of gp130 cytokines and SOCS3 in the wild-type (WT) mice hearts after LPS injection by western blot and real time PCR. Real time PCR revealed that gp130 cytokines were markedly increased after LPS injection. Western blot revealed that STAT3 was markedly phosphorylated and SOCS3 was induced in WT mice hearts after LPS injection. To investigate the role of STAT3 signaling and SOCS3 in LPS-induced LV dysfunction, we generated cardiac-specific SOCS3 knockout mice (SOCS3-KO). Left ventricular ejection fraction (LVEFs) of SOCS3-KO mice were similar to those of WT mice at baseline. LPS (30 mg/kg) impaired cardiac function in both SOCS3-KO and WT, but the magnitude of cardiac dysfunction was much less in SOCS3-KO at 6 hr after injection (LVEF: 28.4±3.9 vs. 43.2±6.1%, p<0.01). SOCS3-KO mice showed the greater survival rate than WT after LPS injection (p<0.01). The duration and intensity of STAT3 phosphorylation after LPS injection were greater in SOCS3-KO mice. The Bcl-xL expression was increased more and the cleaved caspase3 expression was decreased more in SOCS3-KO mice, suggesting that LPS-induced LV dysfunction may be prevented via inhibition of mitochondrial apoptotic signaling pathway in SOCS3-KO mice. Therefore, we examined mitochondrial damage by western blot for cytochrome c (Cyto-c) oxidase (COX) and release of Cyto-c from mitochondria to cytosol after LPS injection. The expressions of COX I and COX II in mitochondria was greater and Cyto-c release in cytosol was less in SOCS3-KO than WT.
Conclusion: Our data show that the deletion of SOCS3 in cardiomyocytes may prevent the LPS-induced LV dysfunction via augmenting the STAT3 signaling and stabilizing mitochondria.
This research has received full or partial funding support from the American Heart Association, National Center.