LAZ3 protects cardiac remodeling in diabetic cardiomyopathy via regulating miR-21/PPARa signaling
LAZ3 protects cardiac remodeling in diabetic cardiomyopathy via regulating miR-21/PPARa signaling
复制标题
LAZ3 通过调节 miR-21/PPARa 信号传导保护糖尿病心肌病的心脏重塑。
DOI：
10.1016/j.bbadis.2018.07.019
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发表时间：
2018-10-01
影响因子：
6.2
通讯作者：
Zhang, Yanzhou
中科院分区：
文献类型：
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作者：
Gao, Lu;Liu, Yuan;Zhang, Yanzhou
糖尿病导致心血管并发症和心脏重塑的发病机制，可导致心力衰竭。我们的目的是评估LAZ 3在糖尿病心肌病（DCM）中的功能作用。采用链脲佐菌素（STZ）诱导糖尿病小鼠模型。诱导三个月后，小鼠接受眶后静脉丛注射过表达LAZ 3的腺相关病毒9（AAV 9）。感染后6周，取出小鼠心脏以评估心脏重塑的程度。LAZ 3在糖尿病小鼠心脏和高糖刺激的心肌细胞中下调。用LAZ 3 siRNA敲低心肌细胞中的LAZ 3降低细胞活力，增加炎症反应，诱导氧化应激和细胞凋亡。通过用腺相关病毒（AAV 9）LAZ 3感染过表达LAZ 3在高糖刺激的体外研究和糖尿病小鼠心脏中保护免受炎症反应、氧化应激和细胞凋亡。我们发现LAZ 3增加了PPARa的活化，PPARa的活化增加了PGC-1a的活化，随后增加了NRF 2的表达和核转位。这一结果通过NRF 2 siRNA和PPARa激活剂证实，因为NRF 2 siRNA消除了LAZ 3过表达的保护作用，而PPARa激活剂在体外和体内研究中都逆转了LAZ 3敲低的恶化表型。此外，LAZ 3降低miR-21的表达，这导致PPARa活化、NRF 2表达和核转位。总之，LAZ 3通过减少miR-21，从而调节PPARa/NRF 2信号传导，防止DCM中的心脏重塑。
Diabetes contributes to cardiovascular complications and the pathogenesis of cardiac remodeling that can lead to heart failure. We aimed to evaluate the functional role of LAZ3 in diabetic cardiomyopathy (DCM). Streptozotocin (STZ) was used to induce a diabetic mouse model. Three months after induction, the mice were subjected to retro-orbital venous plexus injection of adeno-associated virus 9 (AAV9) that overexpressed LAZ3. Six weeks after the infection, mouse hearts were removed to assess the degree of cardiac remodeling. LAZ3 was down-regulated in the diabetic mouse hearts and high glucose stimulated cardiomyocytes. Knock-down of LAZ3 in cardiomyocytes with LAZ3 siRNA reduced cell viability, increased the inflammatory response and induced oxidative stress and cell apoptosis. Overexpression of LAZ3 by infection with adeno-associated virus (AAV9)LAZ3 protected against an inflammatory response, oxidative stress and cell apoptosis in both a high glucose stimulated in vitro study and diabetic mouse hearts. We found that LAZ3 increased the activation of PPARa, which increased PGC-1a activation and subsequently augmented NRF2 expression and nuclear translocation. This outcome was confirmed by NRF2 siRNA and a PPARa activator, since NRF2 siRNA abrogated the protective effects of LAZ3 overexpression, while the PPARa activator reversed the deteriorating phenotype of LAZ3 knockdown in both the in vitro and vivo study. Furthermore, LAZ3 decreased miR-21 expression, which resulted in PPARa activation, NRF2 expression and nuclear translocation. In conclusion, LAZ3 protects against cardiac remodeling in DCM by decreasing miR-21, thus regulating PPARa/NRF2 signaling.