PI K is a lipid kinase and generates phosphatidylinositol tr

PI3K is a lipid kinase and generates phosphatidylinositol-(3,4,5)-trisphosphate, which is a second messenger critical for the translocation of Akt to the cytoplasmic membrane. The phosphorylation of Ser473 Akt is important in the cell survival by regulating the eNOS among other targets (Dimmeler et al., 1999). In this study we found a decrease of P-Akt Cepharanthine in ischemic control hearts and an increase in hearts treated with BZ. The favorable phospholipid environment and/or moderate production of ROS- serving as a signalling molecule- caused by BZ treatment could be the possible mechanisms leading to Akt activation. This rise of Akt phosphorylation by BZ was maintained when this drug was applied under NOS inhibition with L-NAME suggesting that Akt is upstream and promotes eNOS activation.
Conclusions
Conflict of interest
Acknowledgments This study was supported by the Grant PIP0886 from the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) of Argentina to Dra M Nolly and J C Fantinelli.
Introduction Since the first description that short periods of myocardial ischemia induced by alternating cycles of occlusion and reflow of the left circumflex coronary artery resulted in a 75% reduction of myocardial infarct (MI) size in canine hearts [1], accumulating experimental and clinical evidence have provided a variety of therapeutic strategies to increase cardiac tolerance against ischemic insults at early onset [2,3]. In this context, remote ischemic preconditioning (RIPC) appears to be a promising strategy for cardioprotection due to its non-invasive and harmless nature [[4], [5], [6]]. However, even though the elucidation of a large number of signaling pathways underlying RIPC has resulted in valuable advances in the understanding of the pathophysiological mechanisms, ischemic heart disease remains the leading cause of mortality and disability worldwide. Indeed, there are a large number of new therapeutic RIPC strategies currently under investigation to attenuate MI injury with the potential to improve clinical outcomes in patients with acute MI. Although only few RIPC strategies have demonstrated therapeutic benefits, there is compelling evidence that intracoronary nitrite administration, as well as other nitric oxide (NO)-based therapies [7,8] produce remarkable cardioprotection through a NO-dependent pathway [9]. Among the multiple downstream effectors proposed, NO has been viewed as a versatile molecule and a central hub by integrating several intracellular signaling pathways through direct post-translational S-nitrosylation modifications or indirectly by cGMP-dependent signaling pathways [[10], [11], [12]]. Along with other adjunctive therapies, exercise training has gained great attention as a non-pharmacological intervention to prevent cardiovascular-related disorders. However, the majority of published studies only investigate the mechanisms of cardioprotection mediated by long-term exercise training [2,13,14] rather the acute responses to exercise. As recently estimated, cardiovascular adaptations and reduced risk factors induced by long-term exercise training only explain 27% to 41% of the exercise-mediated benefits [15]. Moreover, the cardioprotection produced by a single exercise session lasts between 1 and 5 days [[16], [17], [18]], which suggests acute cellular responses to the exercise bout. Similarly, a single RIPC maneuver induced by 3 cycles of 5 min upper-limb ischemia induced healthy volunteers to release humoral factors that circulate up to 6 days with cardioprotective action in mouse hearts [19]. Resistance exercise (RE) has been highly recommended by several public health guidelines as a complementary non-pharmacological intervention to decrease cardiac risk factors, which in turn, lowers the incidence of non-communicable diseases and increases lifespan. However, there are no reports evaluating whether metabolic pathway exercise modality induces RIPC. Recent data from our laboratory have shown that a single RE session induced an increase in the bioavailability of NO in an intensity- and volume-dependent manner [20,21]. Based on this finding, we aimed to investigate whether RE induces acute cardiac RIPC and to determine if this effect is mediated through a nitric oxide synthase (NOS)-dependent mechanism.