翻譯：周菁  編輯：馮玉蓉  審校：曹瑩

背景：糖尿病加重心肌缺血/再灌注(MI/R)損傷的機(jī)制尚不完全清楚,。脂肪細(xì)胞功能障礙可導(dǎo)致遠(yuǎn)端器官損傷。然而,，功能失調(diào)的脂肪細(xì)胞與MI/R損傷增加的相關(guān)分子機(jī)制仍不清楚,。目前的研究試圖闡明細(xì)胞外小泡(sEV)是否以及如何介導(dǎo)糖尿病脂肪細(xì)胞和心肌細(xì)胞之間的病理聯(lián)系，從而加劇MI/R損傷,。

方法：成年雄性小鼠分別以正常飼料和高脂飼料喂養(yǎng)12周,。將SEV(來自糖尿病血清、糖尿病脂肪細(xì)胞或高糖/高脂（HG/HL）刺激的非糖尿病脂肪細(xì)胞)注射至冠狀動(dòng)脈結(jié)扎遠(yuǎn)端的心肌內(nèi),。注射后48h將小鼠進(jìn)行心肌缺血/再灌注(MI/R)處理,。

結(jié)果：在非糖尿病心臟心肌內(nèi)注射糖尿病血清sEV明顯加重了MI/R損傷，表現(xiàn)為心功能恢復(fù)較差,，梗死面積較大,，心肌細(xì)胞凋亡較多。同樣,，心肌內(nèi)或全身注射糖尿病脂肪細(xì)胞sEV或HG/HL激發(fā)的非糖尿病脂肪細(xì)胞sEV顯著加重MI/R損傷,。糖尿病附睪脂肪移植顯著增加非糖尿病小鼠的MI/R損傷，而給予sEV生物發(fā)生抑制劑顯著減輕糖尿病小鼠的MI/R損傷,。機(jī)制研究證實(shí)miR-130b-3p是糖尿病血清sEV,、糖尿病脂肪細(xì)胞sEV和HG/HL刺激的非糖尿病脂肪細(xì)胞SEV顯著升高的常見分子。糖尿病患者和非糖尿病患者注射糖尿病sEV后,，成熟(但非原發(fā)性)miR-130b-3p顯著增加,。心肌內(nèi)注射miR-130b-3p可顯著加重非糖尿病小鼠的MI/R損傷，而miR-130b-3p抑制劑可顯著減輕糖尿病小鼠的MI/R損傷,。分子生物學(xué)研究證實(shí)AMPKmiR-130b-3p的直接下游靶點(diǎn)為AMPKmiR-130b-3p的α1/α2,、BIRC6和UCP3。過表達(dá)這些分子(特別是AMPKmiR2)可逆轉(zhuǎn)α-130b-3p誘導(dǎo)的促凋亡/心臟損害效應(yīng),。最后,，2型糖尿病患者血漿sEV中miR-130b-3p水平顯著升高。使用糖尿病患者sEV培養(yǎng)的心肌細(xì)胞缺血性損傷顯著加重,，該作用可被miR-130b-3p抑制劑阻斷,。

結(jié)論：我們首次證明了miR-130b-3p在功能障礙的脂肪細(xì)胞來源的sEV中的富集及其對(duì)心肌細(xì)胞中多種抗凋亡/心肌保護(hù)分子的抑制是糖尿病心臟MI/R損傷加重的新機(jī)制,。靶向miR-130b-3p介導(dǎo)的功能失調(diào)性脂肪細(xì)胞和心肌細(xì)胞之間的病理性通訊可能是減輕糖尿病加重MI/R損傷的新策略。

原始文獻(xiàn)來源： 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.