RRC ID 58943
Author Wang Y, Luo W, Han J, Khan ZA, Fang Q, Jin Y, Chen X, Zhang Y, Wang M, Qian J, Huang W, Lum H, Wu G, Liang G.
Title MD2 activation by direct AGE interaction drives inflammatory diabetic cardiomyopathy.
Journal Nat Commun
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.
Volume 11(1)
Pages 2148
Published 2020-5-1
DOI 10.1038/s41467-020-15978-3
PII 10.1038/s41467-020-15978-3
PMID 32358497
PMC PMC7195432
MeSH Animals Blotting, Western Calorimetry Cell Line Diabetes Mellitus, Experimental / immunology* Diabetes Mellitus, Experimental / metabolism* Diabetic Cardiomyopathies / immunology* Diabetic Cardiomyopathies / metabolism* Glycation End Products, Advanced / metabolism* Humans Immunoprecipitation Lymphocyte Antigen 96 / metabolism Male Mice Mice, Inbred C57BL Rats Rats, Sprague-Dawley Signal Transduction / genetics Signal Transduction / physiology Toll-Like Receptor 4 / metabolism
IF 12.121
Times Cited 1
Mice RBRC02388