Effects of insulin replacements, inhibitors of angiotensin, and PKCβ's actions to normalize cardiac gene expression and fuel metabolism in diabetic rats
Effects of insulin replacements, inhibitors of angiotensin, and PKCβ's actions to normalize cardiac gene expression and fuel metabolism in diabetic rats
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DOI：
10.2337/db06-0655
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发表时间：
2007-05-01
期刊：
影响因子：
7.7
通讯作者：
King, George L.
中科院分区：
文献类型：
--
作者：
Arikawa, Emi;Ma, Ronald C. W.;King, George L.
使用高密度寡核苷酸阵列比较对照、未治疗的糖尿病组和接受胰岛细胞移植 (ICT)、蛋白激酶 C (PKC)(3 抑制剂 ruboxistaurin 或 ACE 抑制剂卡托普利) 治疗的糖尿病组大鼠心脏的基因表达。在未治疗的糖尿病心脏和对照心脏之间差异表达的 376 个基因中，包括导致糖尿病心脏中葡萄糖降低和游离脂肪酸利用率增加的关键代谢酶。ICT 或胰岛素替代品通过正常化逆转了这些基因变化。令人惊讶的是，ruboxistaurin 和 ACE 抑制剂均改善了糖尿病大鼠的代谢基因谱（通过实时 RT-PCR 和蛋白质分析证实）并改善了糖尿病心脏中的 PKC 活性，而没有改变循环代谢物。使用 Langendorff 制剂和 C-13 核磁共振波谱进行的功能评估显示，葡萄糖利用率降低了 36%，舒张功能受损。糖尿病大鼠心脏，在心肌细胞中，PKC 抑制减弱了脂肪酸诱导的代谢基因 PDK4 和 UCP3 的增加，并且还阻止了脂肪酸介导的基础和胰岛素刺激的葡萄糖氧化的抑制，因此，PKC(3 或 ACE 抑制剂可能部分地通过心肌中燃料代谢基因表达的正常化来改善糖尿病的心脏代谢和功能。
High-density oligonucleotide arrays were used to compare gene expression of rat hearts from control, untreated diabetic, and diabetic groups treated with islet cell transplantation (ICT), protein kinase C (PKC)(3 inhibitor ruboxistaurin, or ACE inhibitor captopril. Among the 376 genes that were differentially expressed between untreated diabetic and control hearts included key metabolic enzymes that account for the decreased glucose and increased free fatty acid utilization in the diabetic heart. ICT or insulin replacements reversed these gene changes with normalization of hyperglycemia, dyslipidemia, and cardiac PKC activation in diabetic rats. Surprisingly, both ruboxistaurin and ACE inhibitors improved the metabolic gene profile (confirmed by real-time RT-PCR and protein analysis) and ameliorated PKC activity in diabetic hearts without altering circulating metabolites. Functional assessments using Langendorff preparations and C-13 nuclear magnetic resonance spectroscopy showed a 36% decrease in glucose utilization and an impairment in diastolic function in diabetic rat hearts, which were normalized by all three treatments. In cardiomyocytes, PKC inhibition attenuated fatty acid-induced increases in the metabolic genes PDK4 and UCP3 and also prevented fatty acid-mediated inhibition of basal and insulin-stimulated glucose oxidation. Thus, PKC(3 or ACE inhibitors may ameliorate cardiac metabolism and function in diabetes partly by normalization of fuel metabolic gene expression directly in the myocardium.