What is the clinical evidence from this study?

Study design: Other. Population: Diabetic cardiomyopathy. Intervention: MD2 deficiency or inhibition vs. Wild-type or vehicle control. Primary outcome: Cardiac injury, remodeling, and inflammatory signaling.

May 1, 2020Nature Communications136 citationsOpen Access

MD2 activation by direct AGE interaction drives inflammatory diabetic cardiomyopathy

YWYi WangZhejiang Chinese Medical University WLWu LuoUniversity Health Network JHJibo HanHangzhou Normal University

Key Result

High glucose induces extracellular advanced glycation end products (AGEs) that directly bind to MD2, activating the MD2-TLR4 pro-inflammatory signaling complex and driving diabetic cardiomyopathy.

Structured PICO

Does MD2 deficiency or inhibition prevent high glucose-induced inflammatory cardiomyopathy in diabetic models?

Population

A basic science and translational study investigating the role of MD2 and advanced glycation end products in inflammatory diabetic cardiomyopathy using mouse models, cell cultures, and human samples.

Intervention

MD2 deficiency (Md2-/- mice, siRNA knockdown) or MD2 inhibition (L6H21)

Comparator

Wild-type diabetic mice or untreated cells exposed to high glucose

Outcome

Myocardial remodeling, cardiac function, and inflammatory signaling pathways (TLR4 activation)surrogate

MD2 deficiency protects against high glucose-induced inflammatory cardiomyopathy by preventing the direct binding of advanced glycation end products (AGEs) to MD2 and subsequent TLR4 activation.

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.

问 AI

Bookmark

View Full Paper