Adenine nucleotide translocase 1 overexpression protects cardiomyocytes against hypoxia via increased ERK1/2 and AKT activation

作者：Winter Julia; Klumpe Inga; Heger Jacqueline; Rauch Ursula; Schultheiss Heinz Peter; Landmesser Ulf; Doerner Andrea

来源：Cellular Signalling, 2016, 28(1): 152-159.

DOI：10.1016/j.cellsig.2015.11.002

• Adenine nucleotide translocase
• Survival signalling
• ERK1/2
• AKT
• Hypoxia
• Mitochondria

The influence of mitochondrial function on intracellular signalling is currently under intense investigation. In this regard, we analysed the effect of adenine nucleotide translocase 1 (ANT1), which facilitates the exchange of ADP and ATP across the mitochondrial membrane, on cell-protective survival signalling under hypoxia. ANT1 overexpression enhanced the survival rate in hypoxic cardiomyocytes. The effect was related to stabilization of the mitochondrial membrane potential, suppression of caspase 3 activity, and a reduction in DNA fragmentation. Activation of the cell-protective signalling proteins extracellular signal-regulated kinases 1 and 2 (ERK1/2) and protein kinase B (AKT) was substantially higher in hypoxic ANT1-transgenic (ANT1-TG) cardiomyocytes than in wild-type cardiomyocytes. Kinase activation was associated with significantly higher expression of hypoxiainducible factor 1 alpha, which induces glycolytic pathway to stabilize ATP production. Accordingly, ANTI-TG cardiomyocytes exhibited earlier and stronger activation of lactate dehydrogenase and a higher ATP content. Treatment with P0980559 and triciribine, inhibitors of ERK1/2 and Ala activation, respectively, abolished cell protection in hypoxic ANT1-TG cardiomyocytes. Inhibition of ANT by carboxyatractyloside prevented the increase in ERK1/2 and AICT phosphorylation and eliminated the cell protective program in hypoxic ANT1-TG cardiomyocytes.
In conclusion, the cytoprotective effect observed in hypoxic ANT1-overexpressing cardiomyocytes involves an interdependence between ANT1, activation of ERK1/ERK2 and AKT, and induction of the survival processes regulated by these kinases.

• 出版日期2016-1