Li Wei, Leng Yan, Xiong Yonghong, Li Wenyuan, Cai Yin, Xue Rui, Chen Rong, Lei Shaoqing, Xia Zhengyuan, Xia Zhongyuan
Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, China.
Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong SAR, China.
Cell Commun Signal. 2024 May 2;22(1):252. doi: 10.1186/s12964-024-01638-2.
Ischemic postconditioning (IPostC) has been reported as a promising method for protecting against myocardial ischemia-reperfusion (MI/R) injury. Our previous study found that the infarct-limiting effect of IPostC is abolished in the heart of diabetes whose cardiac expression of DJ-1 (also called PARK7, Parkinsonism associated deglycase) is reduced. However, the role and in particular the underlying mechanism of DJ-1 in the loss of sensitivity to IPostC-induced cardioprotection in diabetic hearts remains unclear.
Streptozotocin-induced type 1 diabetic rats were subjected to MI/R injury by occluding the left anterior descending artery (LAD) and followed by reperfusion. IPostC was induced by three cycles of 10s of reperfusion and ischemia at the onset of reperfusion. AAV9-CMV-DJ-1, AAV9-CMV-C106S-DJ-1 or AAV9-DJ-1 siRNA were injected via tail vein to either over-express or knock-down DJ-1 three weeks before inducing MI/R.
Diabetic rats subjected to MI/R exhibited larger infarct area, more severe oxidative injury concomitant with significantly reduced cardiac DJ-1 expression and increased PTEN expression as compared to non-diabetic rats. AAV9-mediated cardiac DJ-1 overexpression, but not the cardiac overexpression of DJ-1 mutant C106S, restored IPostC-induced cardioprotection and this effect was accompanied by increased cytoplasmic DJ-1 translocation toward nuclear and mitochondrial, reduced PTEN expression, and increased Nrf-2/HO-1 transcription. Our further study showed that AAV9-mediated targeted DJ-1 gene knockdown aggravated MI/R injury in diabetic hearts, and this exacerbation of MI/R injury was partially reversed by IPostC in the presence of PTEN inhibition or Nrf-2 activation.
These findings suggest that DJ-1 preserves the cardioprotective effect of IPostC against MI/R injury in diabetic rats through nuclear and mitochondrial DJ-1 translocation and that inhibition of cardiac PTEN and activation of Nrf-2/HO-1 may represent the major downstream mechanisms whereby DJ-1 preserves the cardioprotective effect of IPostC in diabetes.
缺血后适应（IPostC）已被报道为一种预防心肌缺血再灌注（MI/R）损伤的有前景的方法。我们之前的研究发现，在糖尿病心脏中，IPostC的梗死限制作用被消除，其心脏中DJ-1（也称为PARK7，帕金森病相关去糖基化酶）的表达降低。然而，DJ-1在糖尿病心脏中对IPostC诱导的心脏保护作用敏感性丧失中的作用，尤其是潜在机制仍不清楚。
链脲佐菌素诱导的1型糖尿病大鼠通过阻断左前降支动脉（LAD）并随后再灌注来进行MI/R损伤。在再灌注开始时通过三个10秒再灌注和缺血周期诱导IPostC。在诱导MI/R前三周，通过尾静脉注射AAV9-CMV-DJ-1、AAV9-CMV-C106S-DJ-1或AAV9-DJ-1 siRNA以过表达或敲低DJ-1。
与非糖尿病大鼠相比，遭受MI/R的糖尿病大鼠表现出更大的梗死面积、更严重的氧化损伤，同时心脏DJ-1表达显著降低且PTEN表达增加。AAV9介导的心脏DJ-1过表达，但不是DJ-1突变体C106S的心脏过表达，恢复了IPostC诱导的心脏保护作用，并且这种作用伴随着细胞质DJ-1向细胞核和线粒体的转位增加、PTEN表达降低以及Nrf-2/HO-1转录增加。我们的进一步研究表明，AAV9介导的靶向DJ-1基因敲低加重了糖尿病心脏中的MI/R损伤，并且在存在PTEN抑制或Nrf-2激活的情况下，IPostC部分逆转了MI/R损伤的这种加重。
这些发现表明，DJ-1通过细胞核和线粒体DJ-1转位保留了IPostC对糖尿病大鼠MI/R损伤的心脏保护作用，并且抑制心脏PTEN和激活Nrf-2/HO-1可能代表DJ-1在糖尿病中保留IPostC心脏保护作用的主要下游机制。
