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细胞外微小囊泡介导功能失调脂肪细胞与心肌细胞之间的病理通讯是加重糖尿病小鼠缺血再灌注损伤的新机制
翻译：周菁 编辑：冯玉蓉 审校：曹莹
背景：糖尿病加重心肌缺血/再灌注(MI/R)损伤的机制尚不完全清楚。脂肪细胞功能障碍可导致远端器官损伤。然而，功能失调的脂肪细胞与MI/R损伤增加的相关分子机制仍不清楚。目前的研究试图阐明细胞外小泡(sEV)是否以及如何介导糖尿病脂肪细胞和心肌细胞之间的病理联系，从而加剧MI/R损伤。
方法：成年雄性小鼠分别以正常饲料和高脂饲料喂养12周。将SEV(来自糖尿病血清、糖尿病脂肪细胞或高糖/高脂（HG/HL）刺激的非糖尿病脂肪细胞)注射至冠状动脉结扎远端的心肌内。注射后48h将小鼠进行心肌缺血/再灌注(MI/R)处理。
结果：在非糖尿病心脏心肌内注射糖尿病血清sEV明显加重了MI/R损伤，表现为心功能恢复较差，梗死面积较大，心肌细胞凋亡较多。同样，心肌内或全身注射糖尿病脂肪细胞sEV或HG/HL激发的非糖尿病脂肪细胞sEV显著加重MI/R损伤。糖尿病附睾脂肪移植显著增加非糖尿病小鼠的MI/R损伤，而给予sEV生物发生抑制剂显著减轻糖尿病小鼠的MI/R损伤。机制研究证实miR-130b-3p是糖尿病血清sEV、糖尿病脂肪细胞sEV和HG/HL刺激的非糖尿病脂肪细胞SEV显著升高的常见分子。糖尿病患者和非糖尿病患者注射糖尿病sEV后，成熟(但非原发性)miR-130b-3p显著增加。心肌内注射miR-130b-3p可显著加重非糖尿病小鼠的MI/R损伤，而miR-130b-3p抑制剂可显著减轻糖尿病小鼠的MI/R损伤。分子生物学研究证实AMPKmiR-130b-3p的直接下游靶点为AMPKmiR-130b-3p的α1/α2、BIRC6和UCP3。过表达这些分子(特别是AMPKmiR2)可逆转α-130b-3p诱导的促凋亡/心脏损害效应。最后，2型糖尿病患者血浆sEV中miR-130b-3p水平显著升高。使用糖尿病患者sEV培养的心肌细胞缺血性损伤显著加重，该作用可被miR-130b-3p抑制剂阻断。
结论：我们首次证明了miR-130b-3p在功能障碍的脂肪细胞来源的sEV中的富集及其对心肌细胞中多种抗凋亡/心肌保护分子的抑制是糖尿病心脏MI/R损伤加重的新机制。靶向miR-130b-3p介导的功能失调性脂肪细胞和心肌细胞之间的病理性通讯可能是减轻糖尿病加重MI/R损伤的新策略。
原始文献来源： Gan L, Xie D, Liu J, et al. Small Extracellular Microvesicles Mediated Pathological Communications Between Dysfunctional Adipocytes and Cardiomyocytes as a Novel Mechanism Exacerbating Ischemia/Reperfusion Injury in Diabetic Mice.[J]. Circulation 2020 Mar 24;14112(12).DOI：10.1161/CIRCULATIONAHA.119.042640 .
Small Extracellular Microvesicles Mediated Pathological Communications between Dysfunctional Adipocytes and Cardiomyocytes as a Novel Mechanisms Exacerbating Ischemia/Reperfusion Injury in Diabetic Mice
Abstract
Background: Diabetes exacerbates myocardial ischemia/reperfusion (MI/R) injury by incompletely understood mechanisms. Adipocyte dysfunction contributes to remote organ injury. However, the molecular mechanisms linking dysfunctional adipocytes to increased MI/R injury remain unidentified. The current study attempted to clarify whether and how small extracellular vesicles (sEV) may mediate pathological communication between diabetic adipocytes and cardiomyocytes, exacerbating MI/R injury.
Methods: Adult male mice were fed a normal or a high fat diet for 12 weeks. sEV (from diabetic serum, diabetic adipocytes, or high glucose/high lipid (HG/HL)-challenged non-diabetic adipocytes) were injected intramyocardially distal of coronary ligation. Animals were subjected to MI/R 48 hours after injection.
Results: Intramyocardial injection of diabetic serum sEV in the non-diabetic heart significantly exacerbated MI/R injury, as evidenced by poorer cardiac function recovery, larger infarct size, and greater cardiomyocyte apoptosis. Similarly, intramyocardial or systemic administration of diabetic adipocyte sEV or HG/HL-challenged non-diabetic adipocyte sEV significantly exacerbated MI/R injury. Diabetic epididymal fat transplantation significantly increased MI/R injury in non-diabetic mice, whereas administration of a sEV biogenesis inhibitor significantly mitigated MI/R injury in diabetic mice. Mechanistic investigation identified that miR-130b-3p is a common molecule significantly increased in diabetic serum sEV, diabetic adipocyte sEV, and HG/HL-challenged non-diabetic adipocyte sEV. Mature (but not primary) miR-130b-3p was significantly increased in the diabetic and non-diabetic heart subjected to diabetic sEV injection. Whereas intramyocardial injection of a miR-130b-3p mimic significantly exacerbated MI/R injury in non-diabetic mice, miR-130b-3p inhibitors significantly attenuated MI/R injury in diabetic mice. Molecular studies identified AMPKα1/α2, Birc6, and Ucp3 as direct downstream targets of miR-130b-3p. Overexpression of these molecules (particularly AMPKα2) reversed miR-130b-3p induced pro-apoptotic/cardiac harmful effect. Finally, miR-130b-3p levels were significantly increased in plasma sEV from type 2 diabetic patients. Incubation of cardiomyocytes with diabetic patient sEV significantly exacerbated ischemic injury, an effect blocked by miR-130b-3p inhibitor.
Conclusions: We demonstrate for the first time that miR-130b-3p enrichment in dysfunctional adipocyte-derived sEV, and its suppression of multiple anti-apoptotic/cardioprotective molecules in cardiomyocytes, is a novel mechanism exacerbating MI/R injury in the diabetic heart. Targeting miR-130b-3p mediated pathological communication between dysfunctional adipocytes and cardiomyocytes may be a novel strategy attenuating diabetic exacerbation of MI/R injury.
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