Abstract 486: Genetic Deletion of Akt2 and AMPK accentuates Insulin Resistance-Induced Cardiac Contractile Anomalies
BACKGROUND: Insulin resistance is associated with high incidence of cardiovascular diseases although the precise mechanisms remain elusive. Heme oxygenase-1 (HO-1) has recently been proven as a proinflammatory involved in the development of metaflammation (metabolic inflammation). This study was designed to examine the role of HO-1 in insulin resistance-associated cardiac dysfunction and potential roles for two pivotal metabolic signaling molecules AMPK and Akt.
Methods: Whole-body insulin resistance was initiated in wild-type C57BL/6J and AMPK Akt double knockout mice by 8 weeks of sucrose feeding. Contractile and intracellular Ca2+ properties were evaluated in cardiomyocytes using and IonOptix system. Intracellular O2¯ and reactive oxygen species (ROS) were measured.
Results: Sucrose-fed mice displayed impaired glucose tolerance, enhanced oxidative stress, and normal body weight. Cardiac mechanical properties were compromised in sucrose-fed mice including elevated left ventricular end-systolic and reduced factional shortening. Cardiomyocytes from sucrose-fed mice exhibited depressed peak shortening and maximal velocity of shortening/relengthening, prolonged relengthening duration and impaired intracellular Ca2+ homeostasis, the effects of which were exacerbated in AMPK and Akt double knockout mice. In the sucrose-induced insulin resistant mice, levels of HO-1 and ROS were elevated. Metaflammation related cell signaling markers including TNF-α, NF-κB, IL-6 were upregulated in the sucrose-fed mice, whereas the phosphorylation of Akt and AMPK were downregulated. However, the negative feedback from ROS to Akt and AMPK were absent in AMPK Akt double knockout mice. Levels of HO-1, ROS and metaflammation were enhanced in AMPK and Akt double knockout.
Conclusions: These findings indicate that metaflammation may play an important role in cardiac contractile dysfunction associated with glucose intolerance and possibly related to proinflammatory HO-1 signaling. A negative feedback loop was present for AMPK/Akt, the deficiency of which led to exacerbated cardiac contractile anomalies under insulin resistance.
Author Disclosures: Q. Wang: None. M.R. Kandadi: None. J. Ren: None.
- © 2015 by American Heart Association, Inc.