RESUMO
This study aimed to clarify the role of glutamine in atherosclerosis and its participating mechanism. Forty C57BL/6J mice were divided into wild control (wild Con), ApoE- /- control (ApoE- /- Con), glutamine + ApoE- /- control (Glut + ApoE- /- Con), ApoE- /- high fat diet (ApoE- /- HFD), and glutamine + ApoE- /- HFD (Glut + ApoE- /- HFD) groups. The degree of atherosclerosis, western blotting, and multiomics were detected at 18 weeks. An in vitro study was also performed. Glutamine treatment significantly decreased the degree of aortic atherosclerosis (p = 0.03). O-GlcNAcylation (O-GlcNAc), IL-1ß, IL-1α, and pyruvate kinase M2 (PKM2) in the ApoE- /- HFD group were significantly higher than those in the ApoE- /- Con group (p < 0.05). These differences were attenuated by glutamine treatment (p < 0.05), and aggravated by O-GlcNA transferase (OGT) overexpression in the in vitro study (p < 0.05). Multiomics showed that the ApoE- /- HFD group had higher levels of oxidative stress regulatory molecules (guanine deaminase [GUAD], xanthine dehydrogenase [XDH]), proinflammatory regulatory molecules (myristic acid and myristoleic acid), and stress granules regulatory molecules (caprin-1 and deoxyribose-phosphate aldolase [DERA]) (p < 0.05). These differences were attenuated by glutamine treatment (p < 0.05). We conclude that glutamine supplementation might alleviate atherosclerosis through downregulation of O-GlcNAc, glycolysis, oxidative stress, and proinflammatory pathway.
Assuntos
Aterosclerose , Glutamina , Animais , Camundongos , Glutamina/farmacologia , Camundongos Endogâmicos C57BL , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Dieta Hiperlipídica , Apolipoproteínas E , Suplementos Nutricionais , Camundongos KnockoutRESUMO
The present study examined whether atorvastatin, when used for pharmacological postconditioning, attenuated myocardial ischemia-reperfusion (I/R) injury in a manner similar to ischemic postconditioning (I-PostC), that is, by inhibition of endoplasmic reticulum (ER) stress-related apoptosis. In the present study, markers for myocardial injury, infarct area, and hemodynamics, and indicators of ER stress and apoptosis were compared in ischemic and atorvastatin-induced postconditioning as a means of evaluating the protective effect of atorvastatin postconditioning in I/R injury and whether, as in I-PostC, inhibition of ER stress is involved. Both ischemic and atorvastatin-mediated postconditioning significantly decreased indications of cardiac damage and reduced serum concentrations of markers for myocardial injury, reduced the infarct area seen at the end of reperfusion, and improved left ventricular systolic function. We found that high-dose atorvastatin- and I-PostC significantly downregulated expression of glucose-regulating protein 78 and calreticulin (CRT; ER stress markers), expression of C/EBP homologous protein (CHOP), and caspase 12 (markers for ER stress-related apoptosis), and Bax (downstream molecule of CHOP), in the myocardial area at risk. Atorvastatin and I-PostC have similar cardioprotective effects in I/R injury and inhibit the ER stress-related apoptotic pathway.
Assuntos
Apoptose/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Ácidos Heptanoicos/farmacologia , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pós-Condicionamento Isquêmico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Pirróis/farmacologia , Pirróis/uso terapêutico , Animais , Atorvastatina , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: Patients with a recently diagnosed ST-elevation myocardial infarction (STEMI) and implanted coronary drug-eluting stent (DES) who need urgent surgery are at increased risk of surgical bleeding unless aspirin and clopidogrel are discontinued beforehand. However, discontinuation of aspirin and clopidogrel is associated with a high rate of recurrent myocardial infarction, heart failure, and malignant arrhythmias because of stent thrombosis. The main point of debate is how to treat these patients. We hypothesized that perioperative intravenous administration of tirofiban, a GPIIb/IIIa inhibitor, would allow the safe withdrawal of aspirin and clopidogrel without increasing the risk of surgical bleeding. METHODS: Twenty-one patients implanted with a coronary DES after STEMI who underwent urgent surgery were selected for this clinical trial. Tirofiban was used to replace aspirin and clopidogrel (dual antiplatelet drugs) before and after urgent surgery. Major adverse cardiovascular and bleeding events were observed during hospitalization and within 3 months of discharge. RESULTS: Twenty-one patients with recently diagnosed STEMI and implanted DES [median (range) 6 (3-8) months] and high-risk characteristics for stent thrombosis underwent urgent major surgery. Tirofiban was used to replace aspirin and clopidogrel 5 days before surgery, stopped 4 h before surgery, and resumed until oral aspirin and clopidogrel was resumed after surgery. There were no deaths, myocardial infarction, stent thrombosis, or surgical re-exploration because of bleeding during hospitalization and within 3 months of discharge. There was one case of acute left ventricular failure during hospitalization. CONCLUSION: In patients who need urgent surgery after recently diagnosed STEMI and implanted DES, a strategy using tirofiban may allow temporary withdrawal of dual antiplatelet drugs without increasing the risk of bleeding. This conclusion needs to be further confirmed by large-scale randomized clinical trials.