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Letter by Li et al Regarding Article, "Small Extracellular Microvesicles Mediated Pathological Communications Between Dysfunctional Adipocytes and Cardiomyocytes as a Novel Mechanism Exacerbating Ischemia/Reperfusion Injury in Diabetic Mice".

August 18, 2020 e95 Yangxin Li, PhD Fengzhi Ding, MS Zhenya Shen, MD, PhD To the Editor: We read with interest the article by Gan et al,1 who demonstrated that adipocytederived small extracellular vesicles (sEVs; including exosomes and microvesicles) mediate the pathologic communication between dysfunctional adipose tissue and the heart and exacerbate myocardial ischemia/reperfusion injury in obese or diabetic mice. They showed that adipocyte-derived sEVs from diabetic mice contain miR-130b-3p, which suppresses multiple antiapoptotic/cardioprotective molecules in cardiomyocytes to exaggerate myocardial ischemia/reperfusion injury in diabetic mice. This study suggests that strategies targeting abnormal adipocyte sEV production may have great potential in protecting against myocardial ischemia/ reperfusion injury in obesity or diabetes mellitus. In light of these developments in organ–organ crosstalk mediated by circulating sEVs,2,3 we wish to underscore some important additional points about the endocrine function of sEVs from different types of cells in adipose tissue and its impact on heart disease. One recent study showed that adipose tissue macrophage-derived exosomes (ATM-Exos) contain miRNA that can be taken up by insulin target cells in other organs such as liver and muscle and directly affect glucose homeostasis and insulin sensitivity.2 The authors found that lean insulin-sensitive mice treated with obese ATM-Exos developed systemic insulin resistance and glucose intolerance. In contrast, treatment of obese insulin-resistant mice with lean ATM-Exos led to near normalization of glucose tolerance with an improvement in systemic insulin sensitivity. The authors showed that treatment of adipocytes and myocytes with obese ATM-Exos resulted in significant reduction of insulin-stimulated glucose uptake. In light of these findings, it would be interesting to learn whether ATM-Exos are also involved in regulating myocardial ischemia/reperfusion injury in diabetic mice. Understanding the distinct roles of adipocyte-derived sEVs and ATM-Exos may provide new insights into the pathophysiology of ischemic heart disease in patients with diabetes mellitus and lead to the development of novel and more effective therapeutic strategies through the modulation of adipose-derived molecules. One recent study showed that cardiac tissue contains M2 macrophages that can limit adverse remodeling after myocardial infarction.4 Another study demonstrated that adipocyte-derived exosomes promote obesity-induced adipose inflammation by inhibiting M2 macrophage polarization.5 These novel findings highlight the importance of macrophage subsets in regulating heart injury and repair and suggest that the dysfunctional adipocyte-derived sEVs from patients with diabetes mellitus can be taken up by the heart and alter the polarization of macrophages in the cardiac tissue. Therefore, it would be interesting to determine whether sEVs can affect macrophage polarization in the recipient heart in addition to the observed effect on apoptosis. © 2020 American Heart Association, Inc. LETTER TO THE EDITOR Letter by Li et al Regarding Article, “Small Extracellular Microvesicles Mediated Pathological Communications Between Dysfunctional Adipocytes and Cardiomyocytes as a Novel Mechanism Exacerbating Ischemia/ Reperfusion Injury in Diabetic Mice” Circulation