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 AMPKα1/α2, Birc6, and Ucp3 as direct downstream targets of miR-130b-3p. Overexpression of these molecules (particularly AMPKα2) 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.

中文翻译：

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小细胞外微泡介导功能失调的脂肪细胞和心肌细胞之间的病理通讯作为一种新机制加剧糖尿病小鼠的缺血/再灌注损伤。

背景糖尿病通过不完全了解的机制加剧心肌缺血/再灌注(MI/R)损伤。脂肪细胞功能障碍导致远端器官损伤。然而，将功能失调的脂肪细胞与增加的 MI/R 损伤联系起来的分子机制仍未确定。目前的研究试图阐明小细胞外囊泡 (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通讯，从而加剧 MI/R 损伤。方法 给成年雄性小鼠喂食正常或高脂肪饮食 12 周。sEV（来自糖尿病血清、糖尿病脂肪细胞或高糖/高脂攻击的非糖尿病脂肪细胞）被注射到冠状动脉结扎远端的心肌内。动物在注射后 48 小时接受 MI/R。结果表明，在非糖尿病心脏中心肌内注射糖尿病血清 sEV 会显着加剧 MI/R 损伤，这可以通过较差的心脏功能恢复、较大的梗死面积和较大的心肌细胞凋亡来证明。同样，糖尿病脂肪细胞 sEV 或高糖/高脂挑战的非糖尿病脂肪细胞 sEV 的心肌内或全身给药显着加剧了 MI/R 损伤。糖尿病附睾脂肪移植显着增加了非糖尿病小鼠的 MI/R 损伤，而给予 sEV 生物发生抑制剂显着减轻了糖尿病小鼠的 MI/R 损伤。一项机制研究发现，miR-130b-3p 是一种常见分子，在糖尿病血清 sEV、糖尿病脂肪细胞 sEV 和高糖/高脂攻击的非糖尿病脂肪细胞 sEV 中显着增加。在接受糖尿病 sEV 注射的糖尿病和非糖尿病心脏中，成熟（但不是初级）miR-130b-3p 显着增加。miR-130b-3p 模拟物的心肌内注射显着加剧了非糖尿病小鼠的 MI/R 损伤，而 miR-130b-3p 抑制剂显着减轻了糖尿病小鼠的 MI/R 损伤。分子研究确定 AMPKα1/α2、Birc6 和 Ucp3 是 miR-130b-3p 的直接下游靶标。这些分子（特别是 AMPKα2）的过表达逆转了 miR-130b-3p 诱导的促凋亡/心脏有害作用。最后，2 型糖尿病患者血浆 sEV 中的 miR-130b-3p 水平显着升高。将心肌细胞与糖尿病患者 sEV 一起孵育会显着加剧缺血性损伤，这种作用被 miR-130b-3p 抑制剂阻断。结论 我们首次证明，miR-130b-3p 在功能失调的脂肪细胞来源的 sEV 中的富集及其对心肌细胞中多种抗凋亡/心脏保护分子的抑制是一种加剧糖尿病心脏 MI/R 损伤的新机制。靶向 miR-130b-3p 介导的功能失调的脂肪细胞和心肌细胞之间的病理通讯可能是一种减轻糖尿病 MI/R 损伤加重的新策略。