scholarly journals Myocardial Ablation of G Protein–Coupled Receptor Kinase 2 (GRK2) Decreases Ischemia/Reperfusion Injury through an Anti-Intrinsic Apoptotic Pathway

PLoS ONE ◽  
2013 ◽  
Vol 8 (6) ◽  
pp. e66234 ◽  
Author(s):  
Qian Fan ◽  
Mai Chen ◽  
Lin Zuo ◽  
Xiying Shang ◽  
Maggie Z. Huang ◽  
...  
Keyword(s):  
Reperfusion Injury ◽  
G Protein ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Receptor Kinase ◽  
Intrinsic Apoptotic Pathway ◽  
G Protein Coupled Receptor ◽  
Apoptotic Pathway ◽  
G Protein Coupled

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

2018 ◽  
Vol 129 (1) ◽  
pp. 154-162 ◽  
Author(s):  
Soban Umar ◽  
Jingyuan Li ◽  
Kyle Hannabass ◽  
Mylene Vaillancourt ◽  
Christine M. Cunningham ◽  
...  
Keyword(s):  
Ejection Fraction ◽  
Reperfusion Injury ◽  
G Protein ◽  
Lipid Emulsion ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Rate Pressure Product ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

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.

Abstract MP122: Effects of Cardiac Beta3-Adrenoceptors on the Inhibition of G Protein-coupled Receptor Kinase 2 via S-nitrosylation

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Gizem Kayki Mutlu ◽  
Kimberly Ferrero ◽  
Rajika Roy ◽  
Anna Maria Lucchese ◽  
Erhe Gao ◽  
...  
Keyword(s):  
Cardiac Function ◽  
Infarct Size ◽  
G Protein ◽  
Contractile Function ◽  
Ischemia Reperfusion ◽  
The Other ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Other Hand ◽  
G Protein Coupled

G Protein-Coupled Receptor Kinase 2 (GRK2) is a culprit in the loss of cardiac contractile function in heart failure due to β-Adrenoceptor (AR) desensitization after its upregulation. Indeed, its inhibition has been demonstrated to improve cardiac function and increased GRK2 in the heart leads to larger injury after an ischemic insult. Nitric oxide (NO) via S-nitrosothiol (SNO) at residue Cys340 is a reported endogenous inhibitor of GRK2 activity. ß3ARs, on the other hand, are known to be resistant to desensitization by GRK2 and they are upregulated in cardiac pathologies. Activation of ß3ARs can be cardioprotective via NO signalling. Thus, in the present study, we aimed to investigate the interaction between ß3ARs and GRK2 through NO signaling to determine if ß3AR cardioprotection can occur via NO-mediated GRK2 inhibition. We used wild type C57BL/6 mice (WT), global β3AR knockout (KO) mice and GRK2-C340S knockin mice, which harbor a point mutation that changes Cys340 with a serine, meaning all endogenous GRK2 globally cannot be inhibited via NO-mediated S-nitrosylation. We exposed WT, GRK2-C340s KI and β3AR KO mice to ischemia/reperfusion (I/R) injury (40 min ischemia followed by 24 hrs reperfusion). We found that WT mice had significantly diminished cardiac function evaluated by echocardiography and Millar Catheterization, and this was rescued by treating these mice with CL316,243 (a selective β3AR agonist) at the time of reperfusion. On the other hand, GRK2-C340S KI mice did worse after I/R injury compared to WT mice and CL316,243 did not rescue this dysfunction as it did in WT mice. As expected, β3AR KO mice had worsened cardiac function compared to WT mice and CL316,243 had no functional benefit. Infarct size measurements after I/R revealed that β3AR KO mice had larger infarcts than WT mice supporting β3ARs as being protective. Indeed, CL316,243 induced robust cardioprotection in WT mice, reducing infarct size. GRK2-C340S mice had larger infarcts than WT mice and CL316,243 failed to offer any cardioprotection. Thus, β3AR-mediated cardioprotection clearly involves inhibition of GRK2 as part of its therapeutic mechanism and this appears to involve NO-mediated S-nitrosylation.

Sign in / Sign up

Export Citation Format

Share Document