CD133+Exosome Treatment Improves Cardiac Function after Stroke in Type 2 Diabetic Mice.
CD133+Exosome Treatment Improves Cardiac Function after Stroke in Type 2 Diabetic Mice.
复制标题
CD133+外泌体治疗改善2型糖尿病小鼠中风后的心脏功能
DOI：
10.1007/s12975-020-00807-y
复制
发表时间：
2021-03
影响因子：
6.9
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Venkat P;Cui C;Chen Z;Chopp M;Zacharek A;Landschoot-Ward J;Culmone L;Yang XP;Xu J;Chen J
中风后心脏并发症很常见，糖尿病加重了中风后心脏损伤。在这项研究中，我们测试了用从人脐带血来源的CD 133+细胞（CD 133 +Exo）收获的外泌体治疗是否改善2型糖尿病（T2 DM）中风小鼠的心脏功能。将成年（3- 4个月）雄性BKS.Cg-m+/+Leprdb/J（db/db，T2 DM）和非DM（db+）小鼠随机分为假手术组或光血栓性中风组。在中风后3天用磷酸盐缓冲盐水（PBS）或⑶ 133 +Exo（20μg，i.v）处理T2 DM中风小鼠。包括T2 DM假手术组和T2 DM + CD 133 +Exo治疗组作为对照。进行超声心动图检查，并在中风后28天处死小鼠。检测心肌细胞肥大、心肌毛细血管密度、心肌间质纤维化和炎症因子表达。在心脏中测量MicroRNA-126表达及其靶基因表达。与非DM小鼠相比，T2 DM小鼠表现出显著的心脏缺陷，例如左心室射血分数（LVEF）和缩短分数（LVSF）降低、左心室舒张期内径（LVDD）增加和心率降低。与非DM和T2 DM-假手术相比，非DM和T2 DM小鼠的卒中分别显著降低LVEF。与非DM-中风小鼠相比，T2 DM-中风小鼠的心功能障碍更差。与PBS处理的T2 DM-中风小鼠相比，T2 DM-中风小鼠的CD 133 +Exo处理显著改善心脏功能，这通过LVEF增加和LVDD降低来鉴定。此外，CD 133 +Exo治疗显著降低T2 DM-中风小鼠的体重和血糖，但不降低病变体积。T2 DM小鼠的CD 133 +Exo治疗显著降低体重和血糖，但不改善心脏功能。在T2 DM-中风小鼠中，CD 133 +Exo治疗显著降低了心脏组织中的心肌横截面积、间质纤维化、转化生长因子β（TGF-β）、M1巨噬细胞数量以及氧化应激标志物4-HNE（4-羟基壬烯醛）和NADPH氧化酶2（NOX 2）。CD 133 +Exo治疗增加了T2 DM-中风小鼠的心肌毛细血管密度，并在体外上调了内皮细胞毛细血管形成。与来源于内皮细胞的外泌体相比，miR-126在CD 133 +Exo中高度表达。与PBS处理相比，CD 133 +Exo处理显著增加了T2 DM-中风小鼠心脏中miR-126的表达，并降低了其靶基因表达，如Sprouty相关的含EVH 1结构域的蛋白1（Spred-1）、血管细胞粘附蛋白（VCAM）和单核细胞趋化蛋白1（MCP 1）。CD 133 +Exo治疗显著改善T2 DM-中风小鼠的心脏功能。CD 133 +Exo在T2 DM-中风小鼠中的心脏保护作用可能至少部分归因于增加心脏中的miR-126表达并降低其靶蛋白表达、增加心肌毛细血管密度和降低心脏炎症因子表达。
Cardiac complications post-stroke are common, and diabetes exacerbates post-stroke cardiac injury. In this study, we tested whether treatment with exosomes harvested from human umbilical cord blood derived CD133+ cells (CD133+Exo) improves cardiac function in type 2 diabetes mellitus (T2DM) stroke mice. Adult (3–4m), male, BKS.Cg-m+/+Leprdb/J (db/db, T2DM) and non-DM (db+) mice were randomized to sham or photothrombotic stroke groups. T2DM-stroke mice were treated with Phosphate-buffered saline (PBS) or CD133+Exo (20μg, i.v) at 3 days after stroke. T2DM sham, and T2DM+CD133+Exo treatment groups were included as controls. Echocardiography was performed, and mice were sacrificed at 28 days after stroke. Cardiomyocyte hypertrophy, myocardial capillary density, interstitial fibrosis and inflammatory factor expression were measured in heart. MicroRNA-126 expression and its target gene expression were measured in the heart. T2DM mice exhibit significant cardiac deficits such as decreased left ventricular ejection fraction (LVEF) and shortening fraction (LVSF), increased left ventricular diastolic dimension (LVDD) and reduced heart rate compared to non-DM mice. Stroke in non-DM and T2DM mice significantly decreases LVEF compared to non-DM and T2DM-sham, respectively. Cardiac dysfunction is worse in T2DM-stroke mice compared to non-DM-stroke mice. CD133+Exo treatment of T2DM-stroke mice significantly improves cardiac function identified by increased LVEF and decreased LVDD compared to PBS treated T2DM-stroke mice. In addition, CD133+Exo treatment significantly decreases body weight and blood glucose but does not decrease lesion volume in T2DM-stroke mice. CD133+Exo treatment of T2DM mice significantly decreases body weight and blood glucose but does not improve cardiac function. CD133+Exo treatment in T2DM-stroke mice significantly decreases myocardial cross sectional area, interstitial fibrosis, transforming growth factor beta (TGF-β), numbers of M1 macrophages, and oxidative stress markers 4-HNE (4-Hydroxynonenal) and NADPH oxidase 2 (NOX2) in heart tissue. CD133+Exo treatment increases myocardial capillary density in T2DM-stroke mice as well as upregulates endothelial cell capillary tube formation in-vitro. MiR-126 is highly expressed in CD133+Exo compared to exosomes derived from endothelial cells. Compared to PBS treatment, CD133+Exo treatment significantly increases miR-126 expression in heart and decreases its target gene expression such as Sprouty-related, EVH1 domain-containing protein 1 (Spred-1), vascular cell adhesion protein (VCAM), and monocyte chemoattractant protein 1 (MCP1) in the heart of T2DM-stroke mice. CD133+Exo treatment significantly improves cardiac function in T2DM-stroke mice. The cardio-protective effects of CD133+Exo in T2DM-stroke mice may be attributed at least in part to increasing miR-126 expression and decreasing its target protein expression in the heart, increased myocardial capillary density and decreased cardiac inflammatory factor expression.
登录
查看更多内容
影响因子：
3.6
作者：
Distefano G;Sciacca P
通讯作者：
Sciacca P
影响因子：
20.1
作者：
Friedrich, EB;Walenta, K;Werner, N
通讯作者：
Werner, N
影响因子：
8.3
作者：
Chen J;Chopp M
通讯作者：
Chopp M
缺血性中风和心肌梗塞患者中MCP-1趋化因子的血清水平。
影响因子：
4.6
作者：
Arakelyan A;Petrkova J;Hermanova Z;Boyajyan A;Lukl J;Petrek M
通讯作者：
Petrek M
DOI：
10.1152/ajpheart.00238.2018
发表时间：
2018-10-01
影响因子：
4.8
作者：
Alex, Linda;Russo, Ilaria;Frangogiannis, Nikolaos G.
通讯作者：
Frangogiannis, Nikolaos G.