Phosphorylation of GSK-3β Mediates Intralipid-induced Cardioprotection against Ischemia/Reperfusion Injury

Abstract

Background Intralipid, a brand name for the first safe fat emulsion for human use, has been shown to be cardioprotective. However, the mechanism of this protection is not known. Here we investigated the molecular mechanism(s) of Intralipid-induced cardioprotection against ischemia/reperfusion injury, particularly the role of GSK-3β and mitochondiral permeability transition pore in this protective action. Methods In-vivo rat hearts or isolated Langendorff-perfused mouse hearts were subjected to ischemia followed by reperfusion with Intralipid (1% in ex-vivo and one bolus of 20% in in-vivo) or vehicle. The hemodynamic function, infarct size, threshold for the opening of mitochondiral permeability transition pore and phosphorylation levels of Akt/ERK/GSK-3β were measured. Results Administration of Intralipid at the onset of reperfusion resulted in ~70% reduction in infarct size in the in-vivo rat model. Intralipid also significantly improved functional recovery of isolated Langendorff-perfused mouse hearts as the rate pressure product was increased from 2999±863mmHg*beats/min in control to 13676±611 mmHg*beats/min (Mean±SEM) and the infarct size was markedly smaller (18.3±2.4% vs. 54.8±2.9% in control, P<0.01). The Intralipid-induced cardioprotection was fully abolished by LY294002, a specific inhibitor of PI3K, but only partially by PD98059, a specific ERK inhibitor. Intralipid also increased the phosphorylation levels of Akt/ERK1/GSK-3β by 8, 3 and 9 fold, respectively. The opening of mitochondiral permeability transition pore was inhibited by Intralipid as calcium retention capacity was higher in Intralipid group (274.3±8.4nM/mg vs. 168.6±9.6nM/mg control). Conclusions Postischemic treatment with Intralipid inhibits the opening of mitochondiral permeability transition pore and protects the heart through GSK-3β via PI3K/Akt/ERK pathways.

Gastrin Protects Against Myocardial Ischemia/Reperfusion Injury via Activation of RISK (Reperfusion Injury Salvage Kinase) and SAFE (Survivor Activating Factor Enhancement) Pathways

“…Phosphorylation of ERK1/2, AKT, and STAT3 represents RISK and SAFE activation 22. In the present study, the phosphorylation of ERK1/2 (Figure 5A), AKT (Figure 5B), and STAT3 (Figure 5C) was found to be increased in I/R‐injured hearts after treatment with gastrin.…”

“…In the presence of PD98095 (10 μmol/L),23 an ERK1/2 inhibitor, the protective effects of gastrin on the I/R‐injured hearts were decreased, as determined by measurement of cTnI (Figure 6A), LDH release (Figure 6B), apoptosis (TUNEL assay, Figure 6C), cleaved caspase 3 protein (Figure 6D), and cardiac infarct size (Figure 6E). Correspondingly, the protective effects of gastrin were blocked in the presence of LY294002 (50 μmol/L; AKT inhibitor)22 and S3I‐201 (100 μmol/L; STAT3 inhibitor; Figure 6),24 which proves that the RISK and SAFE pathways are involved in mediating the cardioprotective effects of gastrin.…”

Effects of propofol on ischemia-induced ventricular arrhythmias and mitochondrial ATP-sensitive potassium channels

“…Intralipid is a solvent for propofol. Although studies have demonstrated that post-ischemic treatment with intralipid had cardioprotective effects against reperfusion injury [28] , previous studies [12] and our preliminary results demonstrated that intralipid itself did not affect hemodynamics or ischemiainduced arrhythmias. Based on these results, we believe that the use of intralipid as a vehicle did not influence the effects of propofol during ischemic conditions.…”

Intravenous Lipid Emulsion Alters the Hemodynamic Response to Epinephrine in a Rat Model

“…Activation of the G-protein mechanism leads to smooth muscle contraction, and thus vasoconstriction, via calcium influx [26]. ILE has been shown to alter myocardial calcium homeostasis [20,27], but its effect on calcium levels in vascular smooth muscle has not been well studied. ILE has also been shown to enhance alpha 1 mediated vasoconstriction [28] and reduce endothelium-mediated vasodilation after sustained infusion [29].…”