Metabolic and Cardiac Adaptation to Chronic Pharmacologic Blockade of Facilitative Glucose Transport in Murine Dilated Cardiomyopathy and Myocardial Ischemia
Metabolic and Cardiac Adaptation to Chronic Pharmacologic Blockade of Facilitative Glucose Transport in Murine Dilated Cardiomyopathy and Myocardial Ischemia
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DOI：
10.1038/s41598-018-24867-1
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发表时间：
2018-04-24
影响因子：
4.6
通讯作者：
Hruz, Paul W.
中科院分区：
文献类型：
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作者：
Heitmeier, Monique R.;Payne, Maria A.;Hruz, Paul W.
GLUT转基因和基因敲除小鼠为研究葡萄糖易化转运蛋白（GLUT）在心血管和代谢疾病中的作用提供了有价值的见解，但代偿性生理变化可能会阻碍对这些模型的解释。为了确定在衰竭的成年心脏中是否发生了对GLUT抑制的适应，我们用GLUT抑制剂利托那韦长期治疗TG 9小鼠，这是一种扩张型心肌病和心力衰竭的转基因模型。葡萄糖耐量在长期治疗后显著改善，并与脂肪组织视黄醇结合蛋白4（RBP 4）和β-淀粉样蛋白（β-淀粉样蛋白）降低相关。寿命的适度改善与心肌细胞脑钠肽（BNP）表达的降低有关，BNP是心力衰竭严重程度的标志物。利托那韦处理动物左心室（LV）心肌中GLUT 1和-12蛋白表达显著增加。支持在这些组织中从脂肪酸到葡萄糖利用的转换，LV和比目鱼肌中的脂肪酸转运蛋白CD 36和脂肪酸转录调节因子过氧化物酶体增殖物激活受体α（PPAR α）mRNA也减少。慢性利托那韦也增加C57 B1/6小鼠缺血再灌注损伤后的心输出量和dV/dt-d。综上所述，这些数据表明，作为一种手段，以避免在衰竭的心脏有害的变化，在响应慢性GLUT封锁代偿性代谢适应。
GLUT transgenic and knockout mice have provided valuable insight into the role of facilitative glucose transporters (GLUTs) in cardiovascular and metabolic disease, but compensatory physiological changes can hinder interpretation of these models. To determine whether adaptations occur in response to GLUT inhibition in the failing adult heart, we chronically treated TG9 mice, a transgenic model of dilated cardiomyopathy and heart failure, with the GLUT inhibitor ritonavir. Glucose tolerance was significantly improved with chronic treatment and correlated with decreased adipose tissue retinol binding protein 4 (RBP4) and resistin. A modest improvement in lifespan was associated with decreased cardiomyocyte brain natriuretic peptide (BNP) expression, a marker of heart failure severity. GLUT1 and -12 protein expression was significantly increased in left ventricular (LV) myocardium in ritonavir-treated animals. Supporting a switch from fatty acid to glucose utilization in these tissues, fatty acid transporter CD36 and fatty acid transcriptional regulator peroxisome proliferator-activated receptor alpha (PPAR alpha) mRNA were also decreased in LV and soleus muscle. Chronic ritonavir also increased cardiac output and dV/dt-d in C57B1/6 mice following ischemia-reperfusion injury. Taken together, these data demonstrate compensatory metabolic adaptation in response to chronic GLUT blockade as a means to evade deleterious changes in the failing heart.