Effect of Betablockers on the Regulation of PDK (Pyruvate Dehydrogenase Kinase) Gene Expression in Both Normoxic and Hypoxic Myocardium

Journal of Clinical and Basic Cardiology

Tscheliessnig KH¹  Gasser R¹  Porta S¹  Gasser S¹  Holzwart E¹  Roessl U¹  Pieske B¹  Mangge H¹  Friehs I¹  Yates A¹  Mächler H¹  Ablasser K¹  Buehner A¹ 

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关键词: betablockers;    heart;    metabolism;    PDK;   

DOI  :  

学科分类：心脏病和心血管学

来源: Krause & Pachernegg GmbH

【 摘 要 】

Pyruvate dehydrogense kinase isoforms inhibit pyruvate dehydrogenase, which constitutes an important step in glucose metabolism. It is involvedin various phenomena of aging and its expression changes with age – a mechanism that is so far not well-understood. Cardiac metabolism ofglucose is very tightly controlled in order to maintain the variable energy demand that is required by cardiac tissue. Energy metabolism of the cardiacmyocyte can be regulated within seconds up to a few minutes or chronically regulated within the time frame of hours to days. Glucose metabolismis activated in early myocardial ischemia and in response to an increased need of high-energy phosphate in the healthy heart during extremephysical activity. In myocardial ischemia, inhibition of PDK expression would be beneficial in order to shift the myocardial metabolism from theadult towards the fetal phenotype, thus metabolising more glucose than fat to preserve myocardial integrity.Myocardial tissue probes derive from the right auricle of patients undergoing cardiac surgery. A small part of the right auricle is removed whenthe heart is put on extra-corporal circulation. This sample is then placed in cooled Tyrode solution and hypoxia is brought about by switching100 % oxygen to 100 % nitrogen (hypoxia) in one of the 2 chambers. By doing so, we are able to compare ischemic and non-ischemic tissues ofthe same patient. Snap-frozen samples are stored at –170 °C until RNA isolation. Quality of isolated RNA is analysed by means of the Agilent’sBioanalyzer 2100 system. Arrays are scanned with the AB1700 Chemiluminescence Array Reader and images as well as data are processed usingthe PANTHER software.In our microarray experiments, we find that, in particular, PDK isoform 4 is significantly less expressed under nebivolol both during O2perfusion and simulated ischemia, an effect practically negligible under atenolol. Here, nebivolol also exhibits a unique cardioprotective propertydifferent from standard betablockers.We find that without the influence of betablockers there is no significant regulation of PDK expression during myocardial ischemia. There ismerely a trend towards a decrease in PDK gene expression. There is, however a significant difference between the expression of PDK duringmyocardial ischemia in the presence of atenolol (3.62 ± 0.18) and nebivolol (1.97 ± 0.06; + SEM; P ≤0.05): PDK expression is decreasedduring normoxia (trend) and ischemia (significant) in the presence of nebivolol.Here, confirmed by real-time PCR, the finding that PDK gene expression is down-regulated by nebivolol compared to atenolol in normoxia(trend, not statistically significant) and simulated ischemia/hypoxia (statistically significant) may argue for a higher protective, anti-ischemic butalso anti-anginal metabolic potential of nebivolol compared to standard betablockers like atenolol. Especially patients with angina may profit fromthis particular property of nebivolol over atenolol.

【 授权许可】

Unknown