Small Extracellular Microvesicles Mediated Pathological Communications Between Dysfunctional Adipocytes and Cardiomyocytes as a Novel Mechanism Exacerbating Ischemia/Reperfusion Injury in Diabetic Mice
Small Extracellular Microvesicles Mediated Pathological Communications Between Dysfunctional Adipocytes and Cardiomyocytes as a Novel Mechanism Exacerbating Ischemia/Reperfusion Injury in Diabetic Mice
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DOI：
10.1161/circulationaha.119.042640
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发表时间：
2020-03-24
期刊：
影响因子：
37.8
通讯作者：
Wang, Yajing
中科院分区：
文献类型：
--
作者：
Gan, Lu;Xie, Dina;Wang, Yajing
背景：糖尿病加重心肌缺血/再灌注损伤的机制尚不完全清楚。脂肪细胞功能障碍导致远隔器官损伤。然而，功能失调的脂肪细胞与增加的MI/R损伤之间的分子机制仍不清楚。本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：成年雄性小鼠以正常或高脂饮食喂养12周。将SEV(来自糖尿病血清、糖尿病脂肪细胞或高糖/高脂刺激的非糖尿病脂肪细胞)注射到冠状动脉结扎远端的心肌内。结果：非糖尿病大鼠心肌内注射糖尿病血清SEV可明显加重MI/R损伤，表现为心功能恢复较差，心肌梗死面积较大，心肌细胞凋亡率较高。同样，心肌内或全身注射糖尿病脂肪细胞SEV或高糖/高脂刺激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和高糖/高脂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)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。分子研究证实AMPKα1/α2、BIRC6和UCP3是miR-130b-3p的直接下游靶点。这些分子的过表达(特别是AMPKα2)逆转了miR-130b-3p诱导的促凋亡/心脏有害效应。2型糖尿病患者血浆SEV中miR-130b-3p水平显著升高。心肌细胞与糖尿病患者SEV孵育可显著加重心肌缺血损伤，这种作用可被miR-130b-3p抑制剂阻断。结论：我们首次证实，在功能障碍的脂肪细胞来源的SEV中，miR-130b-3p的丰富及其对心肌细胞中多种抗凋亡/心脏保护分子的抑制，是加重糖尿病心脏MI/R损伤的新机制。靶向miR-130b-3p介导的功能紊乱的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的MI/R损伤的新策略。
Background:Diabetes mellitus 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-challenged nondiabetic 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 nondiabetic 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 high glucose/high lipid-challenged nondiabetic adipocyte sEV significantly exacerbated MI/R injury. Diabetic epididymal fat transplantation significantly increased MI/R injury in nondiabetic mice, whereas administration of a sEV biogenesis inhibitor significantly mitigated MI/R injury in diabetic mice. A mechanistic investigation identified that miR-130b-3p is a common molecule significantly increased in diabetic serum sEV, diabetic adipocyte sEV, and high glucose/high lipid-challenged nondiabetic adipocyte sEV. Mature (but not primary) miR-130b-3p was significantly increased in the diabetic and nondiabetic heart subjected to diabetic sEV injection. Whereas intramyocardial injection of a miR-130b-3p mimic significantly exacerbated MI/R injury in nondiabetic mice, miR-130b-3p inhibitors significantly attenuated MI/R injury in diabetic mice. Molecular studies identified AMPK alpha 1/alpha 2, Birc6, and Ucp3 as direct downstream targets of miR-130b-3p. Overexpression of these molecules (particularly AMPK alpha 2) reversed miR-130b-3p induced proapoptotic/cardiac harmful effect. Finally, miR-130b-3p levels were significantly increased in plasma sEV from patients with type 2 diabetes mellitus. 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 antiapoptotic/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.