Abstract
BackgroundIntralipid® administration at reperfusion elicits protection against myocardial ischemia-reperfusion injury. However, the underlying mechanisms are not fully understood.MethodsSprague-Dawley rat hearts were exposed to 15 min of ischemia and 30 min of reperfusion in the absence or presence of Intralipid® 1% administered at the onset of reperfusion. In separate experiments, the reactive oxygen species (ROS) scavenger N-(2-mercaptopropionyl)-glycine was added either alone or with Intralipid®. Left ventricular work and activation of Akt, STAT3, and ERK1/2 were used to evaluate cardioprotection. ROS production was assessed by measuring the loss of aconitase activity and the release of hydrogen peroxide using Amplex Red. Electron transport chain complex activities and proton leak were measured by high-resolution respirometry in permeabilized cardiac fibers. Titration experiments using the fatty acid intermediates of Intralipid® palmitoyl-, oleoyl- and linoleoylcarnitine served to determine concentration-dependent inhibition of complex IV activity and mitochondrial ROS release.ResultsIntralipid® enhanced postischemic recovery and activated Akt and Erk1/2, effects that were abolished by the ROS scavenger N-(2-mercaptopropionyl)glycine. Palmitoylcarnitine and linoleoylcarnitine, but not oleoylcarnitine concentration-dependently inhibited complex IV. Only palmitoylcarnitine reached high tissue concentrations during early reperfusion and generated significant ROS by complex IV inhibition. Palmitoylcarnitine (1 µM), administered at reperfusion, also fully mimicked Intralipid®-mediated protection in an N-(2-mercaptopropionyl)-glycine -dependent manner.ConclusionsOur data describe a new mechanism of postconditioning cardioprotection by the clinically available fat emulsion, Intralipid®. Protection is elicited by the fatty acid intermediate palmitoylcarnitine, and involves inhibition of complex IV, an increase in ROS production and activation of the RISK pathway.
Highlights
IntralipidH is the brand name of the first safe fat emulsion for human use, which was invented by the Swedish medical doctorArvid Wretlind and approved for clinical use in 1962
reactive oxygen species (ROS) Released from the Mitochondrial Electron Transport Chain Trigger Activation of Akt and ERK1/2 during Early Reperfusion in IntralipidH-treated Hearts
We tested whether ROS would be required to activate reperfusion injury salvage kinases (RISK) or signal transducer and activator of transcription 3 (STAT3)
Summary
IntralipidH is the brand name of the first safe fat emulsion for human use, which was invented by the Swedish medical doctor. Arvid Wretlind and approved for clinical use in 1962. IntralipidH is mainly used for parenteral nutrition and serves as solvent of many lipophilic drugs, which would otherwise be insoluble in aqueous solutions and could not be injected intravenously [1]. Rahman and colleagues [3] reported marked protection of the heart against ischemia-reperfusion injury with a 70% reduction in infarct size when IntralipidH was added at high doses (1% in the isolated heart or 5 mL/kg body weight in vivo) at the onset of reperfusion. The fundamental mechanisms causing this marked protection of the heart remain unclear to date. IntralipidH administration at reperfusion elicits protection against myocardial ischemia-reperfusion injury.
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