2014 Volume 7 Issue 1 Pages 30
Background: Protection of ischemia/reperfusion (I/R) induced myocardial injury remains a challenge for clinician. 3, 4-dihydroxyl-phenyl lactic acid (DLA) is a major ingredient of cardiotonic pills®, a undergoing phase Ⅲ clinical trials drug for treatment of cardiovascular diseases in FDA in USA. However whether DLA exerts protective role against I/R and the intracellular target for DLA action remains unclear.
Methods and Results: Male Spragu-Dawley (SD) rats were subjected to left descending artery occlusion for 30 min, followed by reperfusion with or without DLA administration for 90 min. Results showed DLA reduced infarct size, diminished myocardial apoptosis and ameliorated impaired cardiac function and myocardial blood flow (MBF) after I/R. The results of 2-D fluorescence difference gel electrophoresis and activity assay kit revealed that DLA prevented from decrease in NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 10 (NDUFA10) expression, one of the subunits of Complex Ⅰ, blunted the impairment of Complex Ⅰ activity and mitochondrial function. To find the target of DLA, the binding affinity of Sirtuin 1 (SIRT1) to DLA and DLA derivatives with replaced two phenolic hydroxyls were detected using surface plasmon resonance and bilayer interferometry. The observed results demonstrated DLA was able to bind to SIRT1, depending on phenolic hydroxyl.
Conclusions: The present study demonstrated the capability of DLA to bind to and activate SIRT1, which plays an essential role in the cadioprotective effects of DLA. Preserved SIRT1 activity by DLA is responsible for the restored NDUFA10 protein and improved mitochondrial function, eventually leading to repressed infarct size and apoptosis, preserved cardiac function and MBF after I/R.
