Shift from Adult to Fetal Metabolic Phenotype During Prolonged Experimental Myocardial Ischemia: A Study on the Effect of Beta Blockers upon Gene Expression of Transmembrane Glucose Transporters

Journal of Clinical and Basic Cardiology 2009; 12 (1-4): 11-17

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Keywords: Ischämie,  Kardiologie,  Metabolismus,  matabolism,  myocardial ischaemia

The fetal myocardial phenotype predominantly uses glucose for its metabolism, whereas the adult individual mainly metabolises fatty acids. During special conditions, like hypoxia and exercise, the adult phenotype of myocardial metabolism converts to the fetal one, again preferably using glucose as a substrate. It has been shown that a preferentially glucose-oriented cardiac metabolism is beneficial in myocardial ischemia. Our own microarray experiments confirm those data. Here we find that gene expression of biological processes which are associated with glucose metabolism are up-regulated during hypoxia, whereas those associated with fatty acid and amino-acid metabolism are down-regulated. Testing the effects of beta blockers (atenolol and nebivolol) we find a similar shift in well-oxygenized preparations, suggesting that the cardioprotective action of beta blockers is brought about by a shift from the adult to the fetal phenotype of metabolism. Myocardial ischemia thus increases glucose uptake through translocation of GLUT1 and GLUT4 from an intracellular compartment to the sarcolemma. This appears to be beneficial during ischemia and possibly recovery. Here we find that there is no significant regulation with and without the influence of beta blockers during myocardial ischemia – there is, however, a significant difference between the expression of GLUT1 in well-oxygenized preparations with (0.087 ± 0.02) and without nebivolol (0.62 ± 0.02; ± SEM; p ≤ 0.05). Similarly, atenolol led to an increase of GLUT1 expression in well-oxygenated preparations compared to controls: 1.18 ± 0.08 and 0.62 ± 0.02, respectively (± SEM; p < 0.05). While there is no significant regulation with and without the influence of beta blockers during myocardial ischemia, there is, however, a significant difference between the expression of GLUT4 in well-oxygenized preparations with (0.52 ± 0.01) and without nebivolol (0.29 ± 0.02; ± SEM; p ≤ 0.05). Similarly, atenolol led to an increase of GLUT4 expression in well-oxygenated preparations compared to controls: 0.92 ± 0.10 and 0.29 ± 0.02, respectively (± SEM; p < 0.05). These results mirror the increased demand of glucose as a substrate in the presence of beta blockers. Shifting myocardial metabolism to the fetal phenotype has become a new target for anti-anginal treatment in the aging heart, either by augmentation of glucose metabolism or by inhibiting fatty acid metabolism. The latter has been successfully targeted by drugs like trimetazidine and ranolazine. In summary, it has been shown for the first time that some of the anti-anginal effects of beta blockers may possibly be conveyed by their action on GLUT1/4 expression in myocardial cells by facilitating glucose metabolism and in turn causing a shift to the fetal phenotype of metabolism in the adult human heart.