Free Fatty Acid Receptor G-protein–coupled Receptor 40 Mediates Lipid Emulsion-induced Cardioprotection

Abstract

Background We have previously shown that intralipid (lipid emulsion) protects the heart against ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity. However, the precise underlying mechanisms are not fully understood. Here we explored the hypothesis that free fatty acid receptor-1 or G-protein–coupled receptor 40 is expressed in the heart and that cardioprotective effects of lipid emulsion are mediated through G-protein–coupled receptor 40 in two animal models of ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity. Methods Langendorff-perfused male mouse hearts were subjected to ischemia/reperfusion with lipid emulsion alone (1%) or with G-protein–coupled receptor 40 antagonist (GW1100, 10 µM). Additionally, cardiotoxicity was achieved in male rats with bupivacaine bolus (10 mg/kg, IV) followed by lipid emulsion alone (20%, 5 ml/kg bolus, and 0.5 ml · kg–1 · min–1 maintenance, IV) or with GW1100 pretreatment (2.5 mg/kg, IV). Results G-protein–coupled receptor 40 is expressed in rodent hearts. GW1100 abolished lipid emulsion-induced cardioprotection against ischemia/reperfusion in mice because rate pressure product and left ventricular developed pressure were lower than lipid emulsion alone (rate pressure product: 2,186 ± 1,783 [n = 7] vs. 11,607 ± 4,347 [n = 8]; left ventricular developed pressure: 22.6 ± 10.4 vs. 63.8 ± 20; P < 0.0001). Lipid emulsion + GW1100 also demonstrated reduced LV dP/dtmax and LV dP/dtmin (dP/dtmax = 749 ± 386 vs. 2,098 ± 792, P < 0.001; dP/dtmin = −443 ± 262 vs. −1,447 ± 546, P < 0.001). In bupivacaine-induced cardiotoxicity rat model, GW1100 pretreatment had no significant effect on heart rate (HR) and ejection fraction after 30 min (HR: 302 ± 17 vs. 312 ± 38; ejection fraction: 69 ± 3% vs. 73 ± 4%). GW1100 pretreatment, however, prevented lipid-rescue, with no recovery after 10 min. In the control group, lipid emulsion improved HR (215 ± 16 at 10 min) and fully rescued left ventricle function at 10 min (ejection fraction = 67 ± 8%, fractional shortening = 38 ± 6%). Conclusions G-protein–coupled receptor 40 is expressed in the rodent heart and is involved in cardioprotection mediated by lipid emulsion against ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity.

Intralipid postconditioning in patients of Cardiac surgery undergoing cardioPulmonary Bypass (iCPB): study protocol for a randomized controlled trial

“…Because patients with local anesthetic-induced cardiac arrest are considered to be less responsive for standard resuscitation methods, currently infusion of lipid emulsion is considered the primary treatment for local anesthetic toxicity [10,11]. In recent years, another striking experimental finding is that intralipid postconditioning(ILPC) could reduce myocardial I/R injuries and thus improve cardiac function, where intralipid was administered as a bolus at the onset of reperfusion [12][13][14][15][16][17]. So, intralipid may represents a novel and clinically feasible cardioprotective strategy that is highly effective in remodeled hearts.…”

“…It has also played an important role in rescuing the cardiac arrest caused by local anesthetic toxicity, which has been incorporated into several clinical guidelines [8][9][10][11]. In recent years, experimental studies have shown that lipid emulsion infusion just before reperfusion (i.e., intralipid postconditioning, ILPC) could reduce myocardial infarct sizes, improve cardiac function and reduce myocardial I/R injuries [12][13][14][15][16]. Subsequent mechanistic studies define that ILPC acts through the phosphorylation of glycogen synthase kinase-3β via PI3K/Akt/ERK pathways [12][13][14], Caveolin2/STAT3/GSK-3β pathway [15], and ultimately inhibits the opening of mitochondrial permeability transition pore (mPTP), which is essential to mitochondrial calcium overload and reactive oxygen species (ROS).…”

“…Subsequent mechanistic studies define that ILPC acts through the phosphorylation of glycogen synthase kinase-3β via PI3K/Akt/ERK pathways [12][13][14], Caveolin2/STAT3/GSK-3β pathway [15], and ultimately inhibits the opening of mitochondrial permeability transition pore (mPTP), which is essential to mitochondrial calcium overload and reactive oxygen species (ROS). Meanwhile, Umar [16] reported that the cardioprotective effects of lipid emulsion are mediated through G-protein coupled receptor-40 (GPR40) in two animal models of I/R injury and bupivacaine-induced cardiotoxicity. On the other hand, it could simply be a metabolic switch from glucose to fatty acid metabolism that paradoxically protects the heart [5,17].…”

Intralipid postconditioning in patients of Cardiac surgery undergoing cardioPulmonary Bypass (iCPB): study protocol for a randomized controlled trial

“…It has also played an important role in rescuing the cardiac arrest caused by local anesthetic toxicity, which has been incorporated into several clinical guidelines [8][9][10][11]. In recent years, experimental studies have shown that lipid emulsion infusion just before reperfusion (i.e., intralipid postconditioning, ILPC) could reduce myocardial infarct sizes, improve cardiac function and reduce myocardial I/R injuries [12][13][14][15][16]. Subsequent mechanistic studies de ne that ILPC acts through the phosphorylation of glycogen synthase kinase-3β via PI3K/Akt/ERK pathways [12,14,15], Caveolin2/STAT3/GSK-3β pathway [13], and ultimately inhibits the opening of mitochondrial permeability transition pore (mPTP), which is essential to mitochondrial calcium overload and reactive oxygen species (ROS).…”

“…Subsequent mechanistic studies de ne that ILPC acts through the phosphorylation of glycogen synthase kinase-3β via PI3K/Akt/ERK pathways [12,14,15], Caveolin2/STAT3/GSK-3β pathway [13], and ultimately inhibits the opening of mitochondrial permeability transition pore (mPTP), which is essential to mitochondrial calcium overload and reactive oxygen species (ROS). Meanwhile, Umar [16] reported that the cardioprotective effects of lipid emulsion are mediated through G-protein coupled receptor-40 (GPR40) in two animal models of I/R injury and bupivacaine-induced cardiotoxicity.…”