Prevention of hyperglycemia-induced myocardial apoptosis by gene silencing of Toll-like receptor-4 View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2010-12

AUTHORS

Yuwei Zhang, Tianqing Peng, Huaqing Zhu, Xiufen Zheng, Xusheng Zhang, Nan Jiang, Xiaoshu Cheng, Xiaoyan Lai, Aminah Shunnar, Manpreet Singh, Neil Riordan, Vladimir Bogin, Nanwei Tong, Wei-Ping Min

ABSTRACT

BACKGROUND: Apoptosis is an early event involved in cardiomyopathy associated with diabetes mellitus. Toll-like receptor (TLR) signaling triggers cell apoptosis through multiple mechanisms. Up-regulation of TLR4 expression has been shown in diabetic mice. This study aimed to delineate the role of TLR4 in myocardial apoptosis, and to block this process through gene silencing of TLR4 in the myocardia of diabetic mice. METHODS: Diabetes was induced in C57/BL6 mice by the injection of streptozotocin. Diabetic mice were treated with 50 μg of TLR4 siRNA or scrambled siRNA as control. Myocardial apoptosis was determined by TUNEL assay. RESULTS: After 7 days of hyperglycemia, the level of TLR4 mRNA in myocardial tissue was significantly elevated. Treatment of TLR4 siRNA knocked down gene expression as well as diminished its elevation in diabetic mice. Apoptosis was evident in cardiac tissues of diabetic mice as detected by a TUNEL assay. In contrast, treatment with TLR4 siRNA minimized apoptosis in myocardial tissues. Mechanistically, caspase-3 activation was significantly inhibited in mice that were treated with TLR4 siRNA, but not in mice treated with control siRNA. Additionally, gene silencing of TLR4 resulted in suppression of apoptotic cascades, such as Fas and caspase-3 gene expression. TLR4 deficiency resulted in inhibition of reactive oxygen species (ROS) production and NADPH oxidase activity, suggesting suppression of hyperglycemia-induced apoptosis by TLR4 is associated with attenuation of oxidative stress to the cardiomyocytes. CONCLUSIONS: In summary, we present novel evidence that TLR4 plays a critical role in cardiac apoptosis. This is the first demonstration of the prevention of cardiac apoptosis in diabetic mice through silencing of the TLR4 gene. More... »

PAGES

133

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/1479-5876-8-133

DOI

http://dx.doi.org/10.1186/1479-5876-8-133

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1014439577

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/21159162


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