Abstract 158: What’s the Nrf Got To Do With Alcoholic Cardiomyopathy?
2013
The beneficial cardiovascular effects of low alcohol consumption are becoming more clinically evident. This is in sharp contrast with the detrimental ones associated with heavy alcohol drinking. We have previously shown that cardiac inotropy is closely related to the activation of the survival PI3K/Akt pathway. The objective of this study was to assess the role of the PI3K/Akt pathway in mediating the inotropic effects of chronic alcohol consumption. Littermate adult rats were put on a 3-months isocaloric Lieber-Decarli liquid diet with either low alcohol (LA: 5mM) or high alcohol (HA: 100mM) levels. The measured final blood alcohol concentrations were 0.02% and 0.46% respectively. In vivo intra-ventricular catheterization (Scisense/iWorks) of the left ventricle (LV) showed that an improved LV contractility (ESPVR and PRSW) of the LA group while the opposite occurred with the HA group. The alterations in contractility were independent of the afterload as in vitro cellular and sarcomeric inotropic measurements (Ionoptix) showed similar profile to the LV in vivo data. These functional LA effects were correlated with reduced H 2 O 2 levels (as well as SOD-3 activity) and enhanced Akt, NFκB, FOXO-1 and NRF1/2 gene expressions which translated into higher NRF2 protein levels and cardiocyte survival. On the contrary, HA increased H 2 O 2 level (as well as SOD-3 activity) and reduced the Akt, NFκB, FOXO-1 and NRF1/2 gene expressions which translated into lower NRF2 protein levels and cardiocyte survival. In addition, we observed dampening of caspase-3/7 activity with HA which was not affected with LA. We conclude that the improved low alcohol-induced cardiac inotropic function may be mediated through reduction of oxidative stress via Akt/NRF2 activation, which showed opposite expressions with the detrimental high alcohol effects. We also note that cell death occurrences may turn to necrotic pathways as alcohol exposure increases beyond LA levels.
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