Letter by Ren 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”
Authors: Chuanli Ren, Hui Chen, Yuquan Xie
Journal: Circulation (2020)

We were interested to read the article by Gan et al, 1 who showed that miR-130b-3p enrichment in adipocyte-derived small extracellular vesicles (sEVs) is a novel mechanism exacerbating myocardial ischemia/reperfusion (MI/R) injury in diabetic mice.Ying et al 2 found that adipose tissue macrophages in obese mice secrete mi-croRNA (miRNA)-containing exosomes that cause glucose intolerance and insulin resistance, highlighting the origin and cell specificity of exosomes.Fat tissue is a major source of exosomal miRNAs by which sEVs regulate recipient cell function. 3owever, primary adipocytes are difficult to culture, and the purity of sEVs in adipocytes remains a challenge, whereas Gan et al 1 used specific fat-derived miRNAs from serum and transferred them to the myocardium.We are concerned that large quantities of immunoglobulin may contaminate serum, thereby limiting miRNA purity and potential clinical application.Gan et al suggested that overexpression of AMP kinase (AMPK) α1/α2, Birc6, and Ucp3 (particularlyAMPKα2) inhibits harmful miR-130b-3p-induced proapoptotic activity in the myocardium.We raise the following questions: (1) Is miR-130b-3p the most important miRNA targeting these proteins, and how is miR-130b-3p secreted into the blood from adipocyte sEVs?(2) Does monitoring changes in liquid biopsy biomarker miR-130b-3p in human serum or mouse mode in obesity/ diabetes mellitus indicate an association between expression of miR-130b-3p and early diagnosis of MI/R injury?(3) Is AMPKα2 a positive indicator of responsiveness to anti-miR-130b-3p therapy in the diabetic heart with MI/R injury?Gan et al selected miR-130b-3p by global miRNA profiling and confirmed its role in cardiotoxicity because of its higher expression compared with other miR-NAs.We speculate whether miR-130b-3p was the most important regulatory molecule and whether altered expression of other miRNAs should not have been neglected.The functions of these other miRNAs were not verified.Furthermore, there is heterogeneity in screening each gene expression profile, and few studies have described the functions of miR-130b-3p that are related to MI/R injury in diabetes mellitus.miR-130b-3p is significantly increased in serum and adipocyte sEVs in diabetes mellitus and in high glucose/high lipid-challenged nondiabetic adipocyte sEVs.We are eager to know whether miR-130b-3p can be used for early diagnosis of MI/R injury in the diabetic heart, as well as the mechanism of secretion of miR-130b-3p into the blood.AMPK is a key molecular regulator in metabolic disorders and organ damage, whereas adiponectin can protect the heart from MI/R injury through AMPKdependent mechanisms. 4 AMPK is also responsible for activation of glucose uptake and glycolysis and plays an important protective role in reducing damage associated with MI/R injury. 5These reports confirm the importance of AMPK in regulation of the glucose metabolism signaling pathway.We speculate whether