Silencing of miR-195 reduces diabetic cardiomyopathy in C57BL/6 mice.
Silencing of miR-195 reduces diabetic cardiomyopathy in C57BL/6 mice.
复制标题
沉默 miR-195 可减少 C57BL/6 小鼠的糖尿病心肌病。
DOI：
10.1007/s00125-015-3622-8
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发表时间：
2015-08
期刊：
影响因子：
8.2
通讯作者：
Peng T
中科院分区：
文献类型：
--
作者：
Zheng D;Ma J;Yu Y;Li M;Ni R;Wang G;Chen R;Li J;Fan GC;Lacefield JC;Peng T
MicroRNAs （miRs）已被认为是心脏病的潜在治疗靶点。抑制miR-195可阻止棕榈酸盐刺激的心肌细胞凋亡，转基因过表达miR-195可诱导心肌肥厚和心力衰竭。我们在链脲佐菌素（STZ）诱导的1型糖尿病小鼠模型中研究了miR-195沉默是否会减少糖尿病性心肌病。以2月龄雄性C57BL/6小鼠为研究对象，注射STZ诱导1型糖尿病。在stz诱导的1型和db/db 2型糖尿病小鼠心脏中，MiR-195表达增加，其靶蛋白（B细胞白血病/淋巴瘤2和sirtuin 1）水平降低。在stz诱导的小鼠中，系统递送抗miR-195构建物可降低miR-195在心脏中的表达，降低caspase-3活性，降低氧化应激，减轻心肌肥大，改善心肌功能，同时上调B细胞白血病/淋巴瘤2和sirtuin 1。糖尿病降低小鼠心肌毛细血管密度和最大冠状动脉血流量。敲低miR-195可增加糖尿病小鼠心肌毛细血管密度，改善最大冠状动脉血流量。在体外，miR-195的上调充分诱导心肌细胞凋亡，并减弱心脏内皮细胞的血管生成。此外，抑制miR-195可防止NEFA对心脏内皮细胞的凋亡，这是糖尿病的一个重要特征。治疗性沉默miR-195可减少糖尿病患者心肌肥大，改善冠状动脉血流和心肌功能，至少部分是通过减少氧化损伤、抑制细胞凋亡和促进血管生成来实现的。因此，miR-195可能是糖尿病性心脏病的另一种治疗靶点。
MicroRNAs (miRs) have been suggested as potential therapeutic targets for heart diseases. Inhibition of miR-195 prevents apoptosis in cardiomyocytes stimulated with palmitate and transgenic overexpression of miR-195 induces cardiac hypertrophy and heart failure. We investigated whether silencing of miR-195 reduces diabetic cardiomyopathy in a mouse model of streptozotocin (STZ)-induced type 1 diabetes. Type 1 diabetes was induced in C57BL/6 mice (male, 2 months old) by injections of STZ. MiR-195 expression was increased and levels of its target proteins (B cell leukaemia/lymphoma 2 and sirtuin 1) were decreased in STZ-induced type 1 and db/db type 2 diabetic mouse hearts. Systemically delivering an anti-miR-195 construct knocked down miR-195 expression in the heart, reduced caspase-3 activity, decreased oxidative stress, attenuated myocardial hypertrophy and improved myocardial function in STZ-induced mice with a concurrent upregulation of B cell leukaemia/lymphoma 2 and sirtuin 1. Diabetes reduced myocardial capillary density and decreased maximal coronary blood flow in mice. Knockdown of miR-195 increased myocardial capillary density and improved maximal coronary blood flow in diabetic mice. Upregulation of miR-195 sufficiently induced apoptosis in cardiomyocytes and attenuated the angiogenesis of cardiac endothelial cells in vitro. Furthermore, inhibition of miR-195 prevented apoptosis in cardiac endothelial cells in response to NEFA, an important feature of diabetes. Therapeutic silencing of miR-195 reduces myocardial hypertrophy and improves coronary blood flow and myocardial function in diabetes, at least in part by reducing oxidative damage, inhibiting apoptosis and promoting angiogenesis. Thus, miR-195 may represent an alternative therapeutic target for diabetic heart diseases.