Increased expression of Sonic hedgehog restores diabetic endothelial progenitor cells and improves cardiac repair after acute myocardial infarction in diabetic mice
Increased expression of Sonic hedgehog restores diabetic endothelial progenitor cells and improves cardiac repair after acute myocardial infarction in diabetic mice
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Sonic Hedgehog 表达增加可恢复糖尿病小鼠的糖尿病内皮祖细胞并改善急性心肌梗死后的心脏修复
DOI：
10.3892/ijmm.2019.4277
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发表时间：
2019-07
影响因子：
5.4
通讯作者：
Luo Jian Dong
中科院分区：
文献类型：
--
作者：
Xiao Qing;Zhao Xiao Ya;Jiang Ru Chao;Chen Xiu Hui;Zhu Xiang;Chen Kai Feng;Chen Sheng Ying;Zhang Xiao Ling;Qin Yuan;Liu Ying Hua;Luo Jian Dong
糖尿病心肌梗死(DMI)患者内皮祖细胞(EPC)受损与预后不良有关。我们先前的研究表明，受损的Sonic hedgehog(Shh)通路导致糖尿病内皮祖细胞功能不足；然而，Shh通路在基础和缺氧/缺血条件下糖尿病内皮细胞凋亡中的作用尚不清楚。因此，本研究探讨Shh是否能使糖尿病内皮祖细胞恢复活力，从而改善DMI的恶化状态。为此，在雄性C57/BL6小鼠体内注射链脲佐菌素诱导1型糖尿病，并从骨髓中分离糖尿病内皮祖细胞。体外培养内皮祖细胞，观察细胞凋亡、细胞功能和蛋白表达情况。小鼠冠状动脉结扎后即刻注射Shh基因修饰的糖尿病内皮祖细胞(DM-EPCShh)或对照DM-EPCNull。然后检测心功能、毛细血管数量、纤维化和细胞凋亡。首先，体外实验结果表明，在正常或低氧条件下，Shh蛋白作用于糖尿病内皮细胞24 h后，细胞的凋亡率明显减少。Bmi1原癌基因(Bmi1)是一种存在于多种细胞中的抗凋亡蛋白，在正常或低氧条件下，糖尿病内皮祖细胞中Bmi1基因表达降低，Shh蛋白刺激后，Bmi1基因表达上调。当给予Bmi1-siRNA时，Shh蛋白的抗凋亡作用被显著逆转。此外，Bmi1靶向基因P53被证实在糖尿病内皮祖细胞中介导Shh/Bmi1通路的抗凋亡作用。Shh/Bmi1/P53轴也增强了糖尿病的EPC功能。在体内，Shh修饰的糖尿病内皮祖细胞在DMI后3天表现出EPC滞留增加和细胞凋亡减少。在DMI后14天，这些细胞表现为毛细血管密度增加，心肌纤维化减轻，心功能改善。综上所述，本研究结果表明Shh途径通过Shh/Bmi1/P53轴恢复糖尿病内皮祖细胞，抑制心肌细胞凋亡，改善心肌血管生成，从而减轻心肌纤维化，最终恢复心肌修复和心功能。因此，Shh通路可能成为糖尿病心肌缺血自体细胞治疗的潜在靶点。
Damaged endothelial progenitor cells (EPCs) are associated with poor prognosis in diabetic myocardial infarction (DMI). Our previous studies revealed that an impaired Sonic hedgehog (Shh) pathway contributes to insufficient function in diabetic EPCs; however, the roles of the Shh pathway in diabetic EPC apoptosis under basal and hypoxic/ischemic conditions remain unknown. Therefore, the present study investigated whether Shh revitalized diabetic EPCs and consequently improved the deteriorative status of DMI. For this purpose, streptozotocin injection was used in male C57/BL6 mice to induce type-1 diabetes, and diabetic EPCs were isolated from the bone marrow. Apoptosis, cell function, and protein expression were investigated in EPCs in vitro. Mouse hearts were injected with adenovirus Shh-modified diabetic EPCs (DM-EPCShh) or control DM-EPCNull immediately after coronary artery ligation in vivo. Cardiac function, capillary numbers, fibrosis, and cell apoptosis were then detected. First, the in vitro results demonstrated that the apoptosis of diabetic EPCs was reduced following treatment with Shh protein for 24 h, under normal or hypoxic conditions. BMI1 proto-oncogene (Bmi1), an antiapoptotic protein found in several cells, was reduced in diabetic EPCs under normal or hypoxic conditions, but was upregulated after Shh protein stimulation. When Bmi1-siRNA was administered, the antiapoptotic effect of Shh protein was significantly reversed. In addition, p53, a Bmi1-targeted gene, was demonstrated to mediate the antiapoptotic effect of the Shh/Bmi1 pathway in diabetic EPCs. The Shh/Bmi1/p53 axis also enhanced the diabetic EPC function. In vivo, Shh-modified diabetic EPCs exhibited increased EPC retention and decreased apoptosis at 3 days post-DMI. At 14 days post-DMI, these cells presented enhanced capillary density, reduced myocardial fibrosis and improved cardiac function. In conclusion, the present results demonstrated that the Shh pathway restored diabetic EPCs through the Shh/Bmi1/p53 axis, suppressed myocardial apoptosis and improved myocardial angiogenesis, thus reducing cardiac fibrosis and finally restoring myocardial repair and cardiac function in DMI. Thus, the Shh pathway may serve as a potential target for autologous cell therapy in diabetic myocardial ischemia.
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