• Prof. Liang Guang and his team published research result in Nature Communications Revealing the molecular mechanisms of high glucose- and diabetes-induced inflammatory cardiomyopathy
  • Recently, a research article entitled “MD2 activation by direct AGE interaction drives inflammatory diabetic cardiomyopathy” by WMU researcher Professor Liang Guang and his team was officially published in Nature Communications. This study revealed the molecular mechanism of high glucose (HG)-induced inflammatory responses and inflammatory injury and for the first time discovered that the cell-surface myeloid differentiation 2 (MD2) is a new "receptor" for advanced glycation end products (AGEs) in vivo, providing new targets and strategies for preventing and treating diabetic cardiomyopathy. Professor Liang Guang of the School of Pharmaceutical Sciences is the corresponding author of this article, researcher Wang Yi is the first author and co-corresponding author, postdoctoral fellow Luo Wu and master graduate student Han Jibo are co-first authors.

    Diabetic cardiomyopathy (DCM) is one of the major cardiovascular complications of diabetes. About 40% diabetics present cardiac dysfunction without underlying heart disease. At present, the clinical treatment for DCM is limited, and it cannot completely prevent the deterioration of heart function in diabetic patients. In the process of appearance and development of DCM, HG-induced chronic heart inflammation as well as continuous chronic inflammation is the basis of heart damage, however, the molecular mechanism by which HG (or high-concentration glucose) induces heart inflammatory responses remains unknown. Therefore, clearly clarifying the molecular mechanism of this process will help reveal the pathogenesis of DCM and provide new therapeutic targets and strategies for the prevention and treatment of DCM.

    In this research, Liang’s team first shed light on the exact molecular mechanism of diabetes-induced cellular inflammatory responses through myriad experiments: first, high-concentration glucose/ hyperglycemia has a non-enzymatic reaction with serum proteins extracellularly and generates AGEs; then, AGEs directly bind to MD2, changing conformation of MD2, and activate pattern recognition receptor TLR4, contributing to formation of AGEs-MD2-TLR4 complex; this complex activates downstream inflammatory TLR4 signaling pathway, triggers the transcription and production of inflammatory cytokines, and ultimately leads to chronic heart inflammation and dysfunction.

    This article also found that hyperglycemia-induced cardiac inflammatory response through the AGEs-MD2-TLR4 complex occurred simultaneously in cardiomyocytes and infiltrated macrophages in the heart, indicating that both infiltrated immunocytes and local myocardial cells express pattern recognition receptors and contribute to hyperglycemia chronic inflammation. At the same time, gene knockout MD2 or oral small molecule MD2 inhibitors can significantly inhibit hyperglycemia-induced heart inflammation in mice, relieve myocardial damage, and improve cardiac function, suggesting that MD2 can be used as a new target for the prevention and treatment of diabetic cardiomyopathy. In addition, due to the existence of sMD2, a truncated  protein secreted in circulation, the research team found that there was a high level of AGEs-sMD2 complexes in the serum of type 1 and type 2 mouse model of diabetic cardiomyopathy and type 2 diabetic cardiomyopathy patients through serum sample testing, which may provide a new diagnostic indicator for diabetic complications including diabetic cardiomyopathy. It is understood that the research team is currently screening and developing new drugs for preventing and treating diabetes complications with small molecule inhibitors of MD2 / TLR4 / MyD88 chronic inflammatory pathways.

    (Link of the full article: https://www.nature.com/articles/s41467-020-15978-3)