乙二醛酶-1可对抗啮齿动物肺动脉高压中的二羰基应激和右心室功能障碍。
Glyoxylase-1 combats dicarbonyl stress and right ventricular dysfunction in rodent pulmonary arterial hypertension.
作者信息
Prisco Sasha Z, Hartweck Lynn, Keen Jennifer L, Vogel Neal, Kazmirczak Felipe, Eklund Megan, Hemnes Anna R, Brittain Evan L, Prins Kurt W
机构信息
Cardiovascular Division, Department of Medicine, Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, United States.
Pulmonary and Critical Care, Department of Medicine, University of Minnesota, Minneapolis, MN, United States.
出版信息
Front Cardiovasc Med. 2022 Aug 25;9:940932. doi: 10.3389/fcvm.2022.940932. eCollection 2022.
BACKGROUND
Heightened glycolytic flux is associated with right ventricular (RV) dysfunction in pulmonary arterial hypertension (PAH). Methylglyoxal, a glycolysis byproduct, is a highly reactive dicarbonyl that has toxic effects non-enzymatic post-translational modifications (protein glycation). Methylglyoxal is degraded by the glyoxylase system, which includes the rate-limiting enzyme glyoxylase-1 (GLO1), to combat dicarbonyl stress. However, the potential consequences of excess protein glycation on RV function are unknown.
METHODS
Bioinformatics analysis of previously identified glycated proteins predicted how protein glycation regulated cardiac biology. Methylglyoxal treatment of H9c2 cardiomyocytes evaluated the consequences of excess protein glycation on mitochondrial respiration. The effects of adeno-associated virus serotype 9-mediated (AAV9) GLO1 expression on RV function in monocrotaline rats were quantified with echocardiography and hemodynamic studies. Immunoblots and immunofluorescence were implemented to probe the effects of AAV-Glo1 on total protein glycation and fatty acid oxidation (FAO) and fatty acid binding protein levels.
RESULTS
analyses highlighted multiple mitochondrial metabolic pathways may be affected by protein glycation. Exogenous methylglyoxal minimally altered mitochondrial respiration when cells metabolized glucose, however methylglyoxal depressed FAO. AAV9-Glo1 increased RV cardiomyocyte GLO1 expression, reduced total protein glycation, partially restored mitochondrial density, and decreased lipid accumulation. In addition, AAV9-Glo1 increased RV levels of FABP4, a fatty acid binding protein, and hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunits alpha and beta (HADHA and HADHB), the two subunits of the mitochondrial trifunctional protein for FAO. Finally, AAV9-Glo1 blunted RV fibrosis and improved RV systolic and diastolic function.
CONCLUSION
Excess protein glycation promotes RV dysfunction in preclinical PAH, potentially through suppression of FAO.
背景
糖酵解通量增加与肺动脉高压（PAH）中的右心室（RV）功能障碍相关。甲基乙二醛是一种糖酵解副产物，是一种具有高反应性的二羰基化合物，可通过非酶促翻译后修饰（蛋白质糖基化）产生毒性作用。甲基乙二醛通过乙二醛酶系统降解，该系统包括限速酶乙二醛酶-1（GLO1），以对抗二羰基应激。然而，过量蛋白质糖基化对RV功能的潜在影响尚不清楚。
方法
对先前鉴定的糖基化蛋白质进行生物信息学分析，预测蛋白质糖基化如何调节心脏生物学。用甲基乙二醛处理H9c2心肌细胞，评估过量蛋白质糖基化对线粒体呼吸的影响。通过超声心动图和血流动力学研究，定量分析腺相关病毒9型（AAV9）介导的GLO1表达对野百合碱诱导的大鼠RV功能的影响。采用免疫印迹和免疫荧光技术检测AAV-Glo1对总蛋白质糖基化、脂肪酸氧化（FAO）和脂肪酸结合蛋白水平的影响。
结果
分析表明，多种线粒体代谢途径可能受蛋白质糖基化影响。当细胞代谢葡萄糖时，外源性甲基乙二醛对线粒体呼吸的影响最小，但甲基乙二醛会抑制FAO。AAV9-Glo1增加了RV心肌细胞GLO1的表达，减少了总蛋白质糖基化，部分恢复了线粒体密度，并减少了脂质积累。此外，AAV9-Glo1增加了RV中脂肪酸结合蛋白FABP4以及FAO线粒体三功能蛋白的两个亚基α和β（HADHA和HADHB）的水平。最后，AAV9-Glo1减轻了RV纤维化，改善了RV的收缩和舒张功能。
结论
在临床前PAH中，过量蛋白质糖基化可能通过抑制FAO促进RV功能障碍。
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