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Akt activation induced by an antioxidant compound during ischemia-reperfusion
Ambrus Toth1, Robert Halmosi, Krisztina Kovacs
1Department of Biochemistry and Medical Chemistry, University of Pecs Medical School, Pecs, Hungary.
Abstract:
Molecular mechanisms of cardioprotection afforded by modified mexiletine compounds were investigated during ischemia-reperfusion (IR) in Langendorff perfused hearts. Rat hearts were subjected to a global 25 min ischemia followed by reperfusion, either untreated or treated with mexiletine, or three substituted mexiletine derivates (5 muM). A modified mexiletine derivative (H-2693) promoted best the recovery of myocardial energy metabolism (assessed by (31)P NMR spectroscopy) compared to untreated and mexiletine-treated hearts. H-2693 also preserved cardiac contractile function and attenuated the IR-induced lipid peroxidation (TBARS formation) and protein oxidation (carbonyl content). Western blot revealed that H-2693 propagated the phosphorylation of Akt (activation) and its downstream substrate glycogen synthase kinase-3beta (GSK-3beta, inactivation) compared to untreated IR. Parallel treatment with the phosphatidylinositol-3-kinase (upstream activator of Akt) inhibitor wortmannin (100 nM) abolished the beneficial effects of H-2693 on energetics and function, and reduced Akt and GSK-3beta phosphorylation. As a result of the antiapoptotic impacts of Akt activation, H-2693 decreased caspase-3 activity, which was neutralized by wortmannin. Here we first demonstrated that a free radical-entrapping compound could activate the prosurvival Akt pathway beyond its proven ability to scavenge reactive oxygen species. In conclusion, the favorable influence of H-2693 on signaling events during IR may have considerably contributed to its cardioprotective effect.
Insights
Modified mexiletine compound H-2693 protects hearts from ischemia-reperfusion injury by activating the Akt pathway. This novel free radical-scavenging compound enhances myocardial energy metabolism and preserves cardiac function.
Area of Science:
- Cardiovascular Research
- Molecular Pharmacology
- Biochemistry
Background:
- Ischemia-reperfusion (IR) injury significantly impacts cardiac function.
- Mexiletine and its derivatives are explored for cardioprotective potential.
- Understanding the molecular mechanisms of cardioprotection is crucial.
Purpose of the Study:
- To investigate the molecular mechanisms of cardioprotection by modified mexiletine compounds during IR.
- To evaluate the efficacy of a novel derivative, H-2693, in protecting heart function and metabolism.
Main Methods:
- Langendorff perfused rat hearts subjected to global ischemia-reperfusion.
- Treatment with mexiletine, H-2693, or wortmannin (phosphatidylinositol-3-kinase inhibitor).
- Assessment of myocardial energy metabolism ((31)P NMR spectroscopy), contractile function, oxidative stress markers (TBARS, carbonyl content), and signaling pathways (Western blot for Akt, GSK-3beta, caspase-3 activity).
Main Results:
- H-2693 significantly improved myocardial energy metabolism and preserved cardiac contractile function compared to controls.
- H-2693 attenuated ischemia-reperfusion-induced lipid peroxidation and protein oxidation.
- H-2693 activated the prosurvival Akt pathway, leading to GSK-3beta inactivation and decreased caspase-3 activity, effects abolished by wortmannin.
Conclusions:
- Modified mexiletine derivative H-2693 exhibits significant cardioprotective effects during IR.
- Cardioprotection is mediated by the activation of the Akt/GSK-3beta signaling pathway and free radical scavenging.
- H-2693 represents a promising therapeutic agent for mitigating IR-induced cardiac damage.
