Hsp20-Mediated Activation of Exosome Biogenesis in Cardiomyocytes Improves Cardiac Function and Angiogenesis in Diabetic Mice
Hsp20-Mediated Activation of Exosome Biogenesis in Cardiomyocytes Improves Cardiac Function and Angiogenesis in Diabetic Mice
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DOI：
10.2337/db15-1563
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发表时间：
2016-10-01
期刊：
影响因子：
7.7
通讯作者：
Fan, Guo-Chang
中科院分区：
文献类型：
--
作者：
Wang, Xiaohong;Gu, Haitao;Fan, Guo-Chang
1型和2型糖尿病中热休克蛋白（Hsp）表达的降低被认为是糖尿病诱导的器官损伤的主要因素。我们最近发现，糖尿病心肌细胞可以释放有害的外泌体，其中含有低于正常水平的Hsp 20。为了研究这种有害的外泌体是否可以通过提高Hsp 20水平在心肌细胞中进行修饰以变得具有保护性，我们使用了具有心脏特异性Hsp 20过表达的转基因（TG）小鼠模型。给TG和对照野生型（WT）小鼠注射链脲佐菌素（STZ）以诱导糖尿病。我们观察到，热休克蛋白20的过度表达显着衰减STZ引起的心功能不全，肥大，细胞凋亡，纤维化和微血管稀疏。此外，Hsp 20-TG心肌细胞通过Hsp 20与Tsg 101的直接相互作用表现出增加的外泌体的产生/分泌。重要的是，来源于TG心肌细胞的外泌体包裹比WT外泌体更高水平的Hsp 20、p-Akt、存活素和SOD 1，并且保护免受体外高血糖触发的细胞死亡以及体内STZ诱导的心脏不良重塑。最后，GW 4869对外泌体产生的阻断显著抵消了糖尿病小鼠中Hsp 20介导的心脏保护作用。我们的研究结果表明，心肌细胞中Hsp 20的升高可以通过释放工具性外泌体来保护糖尿病心脏。因此，热休克蛋白20基因工程外泌体可能是一种新的治疗糖尿病心肌病的药物。
Decreased heat shock protein (Hsp) expression in type 1 and type 2 diabetes has been implicated as a primary factor contributing to diabetes-induced organ damage. We recently showed that diabetic cardiomyocytes could release detrimental exosomes, which contain lower levels of Hsp20 than normal ones. To investigate whether such detrimental exosomes could be modified in cardiomyocytes by raising Hsp20 levels to become protective, we used a transgenic (TG) mouse model with cardiac-specific overexpression of Hsp20. TG and control wild-type (WT) mice were injected with streptozotocin (STZ) to induce diabetes. We observed that overexpression of Hsp20 significantly attenuated STZ-caused cardiac dysfunction, hypertrophy, apoptosis, fibrosis, and microvascular rarefaction. Moreover, Hsp20-TG cardiomyocytes exhibited an increased generation/secretion of exosomes by direct interaction of Hsp20 with Tsg101. Of importance, exosomes derived from TG cardiomyocytes encased higher levels of Hsp20, p-Akt, survivin, and SOD1 than WT exosomes and protected against in vitro hyperglycemia-triggered cell death, as well as in vivo STZ-induced cardiac adverse remodeling. Last, blockade of exosome generation by GW4869 remarkably offset Hsp20-mediated cardioprotection in diabetic mice. Our results indicate that elevation of Hsp20 in cardiomyocytes can offer protection in diabetic hearts through the release of instrumental exosomes. Thus, Hsp20-engineered exosomes might be a novel therapeutic agent for diabetic cardiomyopathy.