Thursday, November 21, 2024
11/21/2024
Program Summary/Abstract Diabetes is a global epidemic. Many patients with diabetes suffer from and die of heart disease or stroke. Diabetic heart diseases include diabetic cardiomyopathy, obstructive coronary artery disease (CAD), and coronary microvascular disease (CMD, also known as non-obstructive CAD). Obstructive CAD is primarily caused by narrowed vessels due to lipid plaque formation. In contrast, the mechanisms responsible for CMD are microvascular rarefaction, attenuated vasodilatation, and vascular remodeling in small coronary arteries (CAs). Coronary endothelial cell (EC) dysfunction leads to decreased capillary density in the heart and attenuated endothelium-dependent relaxation in CAs, and diabetes causes endothelial dysfunction. However, there is no specific treatment for coronary endothelial dysfunction in patients with diabetes. Our long-term goal is to define the mechanisms of diabetes-associated coronary endothelial dysfunction and ultimately develop novel therapies for CMD in diabetes. Milk fat globule epidermal growth factor (MFGE8) is a glycoprotein primarily secreted from apoptotic cells and initially identified as an immune suppressor by assisting apoptotic cell clearance (efferocytosis). MFGE8 is also capable of promoting angiogenesis and facilitating macrophage reprogramming. MFGE8 administration exerts beneficial effects on cardiovascular disease, including anti-inflammation, tissue repairing, and compensated cardiac hypertrophy; however, the role of MFGE8 in coronary endothelial dysfunction and CMD in diabetes has never been investigated. The objective of this study is to examine whether and how MFGE8 improves CMD in diabetes. Our preliminary data show that i) cardiac ECs from diabetic mice and diabetic patients displayed lower MFGE8 levels than their controls, ii) Mfge8-/- mice exhibited reduced coronary flow velocity reserve (CFVR), iii) inhibition of MFGE8 attenuated endothelium-dependent relaxation in CAs and endothelial migration, iv) chronic administration of MFGE8 in diabetic mice improved CFVR accompanied with increased capillary density in the heart, v) macrophages enabled to engulf apoptotic ECs ex vivo, and MFGE8 pretreatment increased macrophage efferocytosis of ECs, and vi) MFGE8 administration in diabetic mice facilitated reprogramming of macrophages to an anti-inflammatory phenotype. Based on these data, we hypothesize that MFGE8 administration is a novel therapeutic strategy in diabetic patients with CMD by improving coronary endothelial function and enhancing macrophage engulfment of apoptotic ECs in the heart where MFGE8 level is reduced in coronary ECs. Three Specific Aims are proposed to test our novel hypothesis: 1) to define the role of MFGE8 in coronary endothelial dysfunction and CMD in diabetic mice, 2) to determine the molecular mechanisms by which MFGE8 regulates coronary endothelial function in diabetes, and 3) to investigate the role of MFGE8-mediated macrophage efferocytosis of coronary ECs in endothelial dysfunction in diabetes. Completion of this study will provide important insights into the development of new and effective therapeutic interventions for CMD in diabetes.
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