Metabolomic analysis of two different models of delayed preconditioning

Abstract

Recently we described an ischemic preconditioning induced by repetitive coronary stenosis, which is induced by 6 episodes of non-lethal ischemia over 3 days, and which also resembles the hibernating myocardium phenotype. When compared with traditional second window of ischemic preconditioning using DNA microarrays, many genes which differed in the repetitive coronary stenosis appeared targeted to metabolism. Accordingly, the goal of this study was to provide a more in depth analysis of changes in metabolism in the different models of delayed preconditioning, i.e., second window and repetitive coronary stenosis. This was accomplished using a metabolomic approach based on liquid chromatography-mass spectrometry (LC-MS) and gas chromatography-mass spectrometry (GC-MS) techniques. Myocardial samples from the ischemic section of porcine hearts subjected to both models of late preconditioning were compared against sham controls. Interestingly, although both models involve delayed preconditioning, their metabolic signatures were radically different; of the total number of metabolites that changed in both models (135 metabolites) only 7 changed in both models, and significantly more, p<0.01, were altered in the repetitive coronary stenosis (40%) than in the second window (8.1%). The most significant changes observed were in energy metabolism, e.g., phosphocreatine was increased 4 fold and creatine kinase activity increased by 27.2%, a pattern opposite from heart failure, suggesting that the repetitive coronary stenosis and potentially hibernating myocardium have enhanced stress resistance capabilities. The improved energy metabolism could also be a key mechanism contributing to the cardioprotection observed in the repetitive coronary stenosis and in hibernating myocardium.

Effects of Near-Infrared Light on Cerebral Bioenergetics Measured with Phosphorus Magnetic Resonance Spectroscopy

“…46 Since the brain evolved to support robust metabolic responses in active neurons and circuits while minimizing resting global energy expenditure, 47 a PBM-induced increase in brain PCr levels could help supply the on-demand energy necessary for rapid circuit activation, thereby improving brain func-tion, as reported previously. 10,[21][22][23][24][25][26][27][28] PCr elevations in the heart and brain have been associated with preconditioning stimuli, [48][49][50] and preconditioning effects of PBM have been described in multiple tissues. 1,13,46 Accordingly, it is possible that PBM-associated elevations in the PCr/b-NTP ratio and PCr we detected at the scan session 2 baseline could reflect a cortical preconditioning effect of TLT.…”

Molecular and Cellular Basis of Viable Dysfunctional Myocardium

“…67 The results of a recent metabolomic analysis of ischemic VD pig myocardium were supportive of these data, showing a reduction in TCA cycle metabolites α-ketoglutarate, succinate, fumarate and malate. 68 Moreover, the intermediates of lipid metabolism, carnitine, acetylcarnitine and palmitoylcarnitine, were also reduced in VD myocardium. 68 Thus, mitochondrial oxidative phosphorylation is consistently suppressed in VD myocardium of humans and animals.…”

“…68 Moreover, the intermediates of lipid metabolism, carnitine, acetylcarnitine and palmitoylcarnitine, were also reduced in VD myocardium. 68 Thus, mitochondrial oxidative phosphorylation is consistently suppressed in VD myocardium of humans and animals.…”

“…Others have characterized the suppression of mitochondrial function as an adaptive mechanism, based on preservation of multiple energetic indices despite the overall reduction in metabolic rate. 48, 64, 67, 68, 88 These include preserved phosphocreatine (PCr)-to-ATP ratio, 67, 68, 88 , maintenance of the ATP-to-ADP ratio, 88 and a slower rate of ATP depletion, 88 suggestive of energetic efficiency of the VD heart. Finally, despite reduced mitochondrial function and lower O 2 consumption at rest, VD myocardium was able to increase its metabolism and utilize diverse energy substrates in response to an increased workload without the development of ischemia.…”

Post-Genomic Methodologies and Preclinical Animal Models: Chances for the Translation of Cardioprotection to the Clinic

“…As such, the frequency and magnitude of the metabolite changes was higher in those animals subjected to repetitive coronary stenosis (6 episodes of non-lethal ischemia over 3 days prior to the ischemic insult) as compared to those that underwent second window of ischemic preconditioning (two episodes of total left anterior descending coronary artery occlusion for 10 min and 10 min of reperfusion, followed by 24 h of reperfusion). Most interestingly, most of the altered cardiac metabolites found in repetitive coronary stenosis were linked to mechanisms known to improve energy metabolism [72]. Regarding lipidomics, we have recently reported that the attenuation of HDL-related cardioprotection in the setting of hypercholesterolemia might be associated with lipidomic changes in the HDL micelles, losing phosphatidylcholine-lipid species (involved in HDL functionality) and gaining cholesteryl esters (involved in HDL maturation and loss of function) [58].…”