Based on the concept of a “gradual wake-up”, we specifically hypothesized that Intralipid ® would inhibit electron flux and thus generate ROS at the onset of reperfusion. Hence we set out to investigate the activities of the respiratory complexes as possible targets of Intralipid®, and further explored the role of ROS. This hypothesis has not been tested so far and the precise mechanisms of Intralipid®-induced protection remain elusive. Therefore, we hypothesized that the formation of reactive oxygen species (ROS) due to inhibition of the electron transport chain would activate reperfusion injury salvage kinases (RISK) or signal transducer and activator of transcription 3 (STAT3). While such an energy boost from fatty acid oxidation may foster postischemic recovery, mechanisms previously reported for many types of postconditioning should also be considered in Intralipid®-mediated cardioprotection. Consistent with this concept is the notion that increased fatty acid oxidation plays a beneficial role in the recovery of Intralipid®-rescued hearts exposed to lethal doses of local anesthetics. Other studies also support the importance of fat oxidation under conditions of ischemia/reperfusion, , and raise the possibility that by increasing energy supply, administration of Intralipid® at the onset of reperfusion could help secure energy production and enhance postischemic recovery. In contrast to this “iconic principle” in cardioprotection by metabolic interventions, we have recently reported that infarct-remodeled hearts with limited oxidative capacity accelerate fatty acid oxidation for ATP production and not glucose oxidation after conditioning against ischemia/reperfusion injury. Increasing fatty acid oxidation under ischemia/reperfusion conditions is usually regarded as detrimental, while increasing glucose oxidation and concomitantly reducing fatty acid oxidation (Randle cycle) is considered beneficial. However, the fundamental mechanisms causing this marked protection of the heart remain unclear to date. That study and a follow-up study from the same group observed activation of protection signaling (Akt, ERK1/2) and phosphorylation (and inhibition) of GSK3β with subsequent increased Ca 2+ retention capacity of mitochondria, suggesting inhibition of the permeability transition pore. More recently, Rahman and colleagues reported marked protection of the heart against ischemia-reperfusion injury with a 70% reduction in infarct size when Intralipid® was added at high doses (1% in the isolated heart or 5 mL/kg body weight in vivo) at the onset of reperfusion. As rescue therapy, Intralipid® was also found to accelerate detoxification of overdosed lipophilic drugs such as local anesthetics, drugs targeting the central nervous system and various Ca 2+ channel blockers by acting as a “lipid sink”. In the clinical setting, Intralipid® 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. The major fatty acid constituents are linoleic acid (C18∶2, ∼60%), oleic acid (C18∶1, ∼30%) and palmitic acid (C16∶0, ∼10–15%). Beside phospholipids (1.2%) and glycerol (2.2%), it consists of a mixture of neutral triglycerides. Intralipid® 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.
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