Metallothionein prevents diabetes-induced cardiac pathological changes, likely via the inhibition of succinyl-CoA:3-ketoacid coenzyme A transferase-1 nitration at Trp374

American Journal of Physiology - Endocrinology and Metabolism - Tập 304 Số 8 - Trang E826-E835 - 2013
Weitao Cong1,2, Weide Ma1,3,2, Ting Zhao1,2, Zhongxin Zhu1,2, Yuehui Wang4, Yi Tan1,5, Xiaokun Li1,2, Litai Jin1,2, Lu Cai1,5
1Chinese-American Research Institute for Diabetic Complications, Wenzhou Medical College, Zhejiang, China;
2School of Pharmaceutical Science, Wenzhou Medical College, Wenzhou, China
3Laboratory of Gynecology and Obstetrics, People's Hospital of Wenzhou, Zhejiang, China;
4Department of Cardiovascular Disorders, the Second Hospital of Jilin University, Changchun, China; and
5Kosair Children's Hospital Research Institute, Department of Pediatrics, University of Louisville School of Medicine, Louisville, Kentucky

Tóm tắt

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 Tyr76, Tyr117, Tyr135, Tyr226, Tyr368, and Trp374, only Tyr76and Trp374were found to be located in the active site by three-dimensional structure modeling. However, only Trp374showed 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 Trp374.

Từ khóa


Tài liệu tham khảo

10.1016/j.freeradbiomed.2009.12.009

10.1016/j.freeradbiomed.2006.06.007

10.1074/jbc.C000593200

10.2337/diabetes.54.6.1829

10.1016/j.jacc.2006.07.022

10.1002/elps.200290020

10.2337/db06-1596

10.1016/j.bbadis.2011.01.015

10.1203/00006450-199710000-00013

10.1016/j.ymgme.2007.12.006

Gokulrangan G, 2007, J Neurochem, 100, 1494, 10.1111/j.1471-4159.2006.04334.x

10.1042/bj2400049

10.1139/Y10-016

10.1016/j.jasms.2010.05.009

10.1016/j.freeradbiomed.2010.01.010

10.1093/cvr/cvp085

10.1073/pnas.141222598

10.1016/j.abb.2010.12.011

10.1620/tjem.215.227

10.1073/pnas.0307446101

10.1021/bi7001482

10.1016/j.abb.2008.11.007

10.1001/jama.289.13.1675

10.1016/S0002-9440(10)62949-5

10.1007/s00592-010-0180-x

10.1074/jbc.M303734200

10.1152/ajpheart.2001.281.6.H2289

10.1124/pr.54.4.619

10.1074/jbc.M303139200

10.2337/db08-1697

10.1021/pr100349g

10.1042/bj1210041

10.1074/jbc.273.23.14085

10.1152/ajpendo.90234.2008