MD2 activation by direct AGE interaction drives inflammatory diabetic cardiomyopathy

Yi Wang (), Wu Luo, Jibo Han, Zia A. Khan, Qilu Fang, Yiyi Jin, Xuemei Chen, Yali Zhang, Meihong Wang, Jianchang Qian, Weijian Huang, Hazel Lum, Gaojun Wu and Guang Liang ()
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Yi Wang: the First Affiliated Hospital of Wenzhou Medical University
Wu Luo: Wenzhou Medical University
Jibo Han: the First Affiliated Hospital of Wenzhou Medical University
Zia A. Khan: Wenzhou Medical University
Qilu Fang: Wenzhou Medical University
Yiyi Jin: Wenzhou Medical University
Xuemei Chen: Wenzhou Medical University
Yali Zhang: Wenzhou Medical University
Meihong Wang: Wenzhou Medical University
Jianchang Qian: Wenzhou Medical University
Weijian Huang: the First Affiliated Hospital of Wenzhou Medical University
Hazel Lum: Wenzhou Medical University
Gaojun Wu: the First Affiliated Hospital of Wenzhou Medical University
Guang Liang: the First Affiliated Hospital of Wenzhou Medical University

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract Hyperglycemia activates toll-like receptor 4 (TLR4) to induce inflammation in diabetic cardiomyopathy (DCM). However, the mechanisms of TLR4 activation remain unclear. Here we examine the role of myeloid differentiation 2 (MD2), a co-receptor of TLR4, in high glucose (HG)- and diabetes-induced inflammatory cardiomyopathy. We show increased MD2 in heart tissues of diabetic mice and serum of human diabetic subjects. MD2 deficiency in mice inhibits TLR4 pathway activation, which correlates with reduced myocardial remodeling and improved cardiac function. Mechanistically, we show that HG induces extracellular advanced glycation end products (AGEs), which bind directly to MD2, leading to formation of AGEs-MD2-TLR4 complex and initiation of pro-inflammatory pathways. We further detect elevated AGE-MD2 complexes in heart tissues and serum of diabetic mice and human subjects with DCM. In summary, we uncover a new mechanism of HG-induced inflammatory responses and myocardial injury, in which AGE products directly bind MD2 to drive inflammatory DCM.

Date: 2020
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DOI: 10.1038/s41467-020-15978-3

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