Abstract 15517: Deficiency of AMPK Exacerbates Lipopolysaccharide-Induced Cardiac Contractile Dysfunction: The Role of Autophagy
Lipopolysaccharide (LPS),the main component of the gram-negative bacteria, is the culprit player responsible for sepsis-induced cardiac dysfunction. Accumulating evidence has indicated a pivotal role of AMP-activated protein kinase (AMPK) in inflammatory responses and pathology under sepsis. To this end, this study was designed to examine the role of AMPK deficiency in LPS-induced cardiac contractile dysfunction and the underlying mechanism(s) with a focus on autophagy. Wild-type (WT) and transgenic mice over-expressing a kinase-dead (KD) a2 isoform (K45R mutation) of AMPK were challenged with LPS (4mg/kg, i.p.). Cardiac function was evaluated using echocardiography and cardiomyocyte mechanics. MAPK and autophagic signaling proteins, including AMPK, mTOR, ULK1, Atgs, LC3B, LAMP1 and Rab7and P62, were examined. LPS challenge compromised cardiac contractile function accompanied by decreased phosphorylation of AMPK as well as increased p38MAPK and ERK, alongwith autophagosome maturation dysfunction (increased LC3BIIand p62, and decrease of LAMP1), the effect of which was exacerbated by AMPK deficiency.Moreover, the p38 and ERK inhibitors, SB203580 and U0126, respectively,partially reversed LPS-induced autophagy (LC3B expression and puncta), reduced the expression of P62 and restored cardiac contractile function. Inhibition of autophagosome fusion with lysosomal failed to influence the LPS-induced contraction anomalies. Nonetheless, the mTOR inhibitor rapamycin alleviated LPS-induced cardiac dysfunction and interruption of autophagic flux. These data have implicated that LPS triggered cardiomyocyte dysfunction associated with blockade of autophagyflux. AMPK deficiency exacerbated LPS-induced interruption of autophagy flux possibly through accentuating activation of p38MAPK and ERK.
- © 2013 by American Heart Association, Inc.