Metallothionein prevents diabetes-induced cardiac pathological changes, likely via the inhibition of succinyl-CoA:3-ketoacid coenzyme A transferase-1 nitration at Trp374
Metallothionein prevents diabetes-induced cardiac pathological changes, likely via the inhibition of succinyl-CoA:3-ketoacid coenzyme A transferase-1 nitration at Trp374
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DOI：
10.1152/ajpendo.00570.2012
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发表时间：
2013-04-01
影响因子：
5.1
通讯作者：
Cai, Lu
中科院分区：
文献类型：
--
作者：
Cong, Weitao;Ma, Weide;Cai, Lu
金属硫蛋白预防糖尿病心脏病变，可能是通过抑制Trp处的琥珀酰辅酶A：3-酮酸辅酶A转移酶-1硝化(374)。Am J生理学内分泌Metab 304：E826-E835,2013。2013年2月26日首次出版；DOI：10.1152/ajpendo.00570.2012。-我们先前证明，金属硫蛋白(MT)介导的对糖尿病引起的心脏组织病变的保护与抑制超氧化物生成和蛋白质硝化有关。本研究通过鉴定野生型(WT)小鼠糖尿病心脏中存在的硝化蛋白组和心脏特异性MT过表达转基因(MT-TG)小鼠心脏中不存在的硝化蛋白组，研究了哪些糖尿病硝化蛋白(S)介导了这些病理变化的发生。在链脲佐菌素诱导糖尿病后2、4、8和16wk，WT和MT-TG糖尿病大鼠心脏组织病理学检查显示心脏结构紊乱和重构，超氧化物生成显著增加，3-硝基酪氨酸积聚。用质谱仪鉴定了一个58 kDa的硝化蛋白，即琥珀酰辅酶A：3-酮酸辅酶A转移酶-1(SCOT)。尽管两种类型的小鼠之间总的SCOT表达没有显著差异，但糖尿病WT小鼠心脏中的SCOT硝化含量显著增加，催化活性显著降低。虽然在Tyr(76)、Tyr(117)、Tyr(135)、Tyr(226)、Tyr(368)和Trp(374)处发现了SCOT硝化位点，但通过三维结构模拟发现只有Tyr(76)和Trp(374)位于活性中心。然而，只有Trp(374)在WT和MT-TG糖尿病心脏之间显示出显著不同的硝化水平。这些结果表明，MT预防糖尿病引起的心脏组织病变很可能是通过抑制Trp(374)上的Scot硝化而实现的。
Cong WT, Ma WD, Zhao T, Zhu ZX, Wang YH, Tan Y, Li XK, Jin LT, Cai L. Metallothionein prevents diabetes-induced cardiac pathological changes, likely via the inhibition of succinyl-CoA: 3-ketoacid coenzyme A transferase-1 nitration at Trp(374). Am J Physiol Endocrinol Metab 304: E826-E835, 2013. First published February 26, 2013; doi:10.1152/ajpendo.00570.2012.-We previously demonstrated that metallothionein (MT)-mediated protection from diabetes-induced pathological changes in cardiac tissues is related to suppression of superoxide generation and protein nitration. The present study investigated which diabetes-nitrated protein(s) mediate the development of these pathological changes by identifying the panel of nitrated proteins present in diabetic hearts of wild-type (WT) mice and not in those of cardiac-specific MT-overexpressing transgenic (MT-TG) mice. At 2, 4, 8, and 16 wk after streptozotocin induction of diabetes, histopathological examination of the WT and MT-TG diabetic hearts revealed cardiac structure derangement and remodeling, significantly increased superoxide generation, and 3-nitrotyrosine accumulation. A nitrated protein of 58 kDa, succinyl-CoA: 3-ketoacid CoA transferase-1 (SCOT), was identified by mass spectrometry. Although total SCOT expression was not significantly different between the two types of mice, the diabetic WT hearts showed significantly increased nitration content and dramatically decreased catalyzing activity of SCOT. Although SCOT nitration sites were identified at Tyr(76), Tyr(117), Tyr(135), Tyr(226), Tyr(368), and Trp(374), only Tyr(76) and Trp(374) were found to be located in the active site by three-dimensional structure modeling. However, only Trp(374) showed a significantly different nitration level between the WT and MT-TG diabetic hearts. These results suggest that MT prevention of diabetes-induced pathological changes in cardiac tissues is most likely mediated by suppression of SCOT nitration at Trp(374).