Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing, 401331, China; Henan Key Laboratory of Medical Tissue Regeneration, College of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, Henan, 453003, China.
Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing, 401331, China.
Exp Eye Res. 2021 Jun;207:108559. doi: 10.1016/j.exer.2021.108559. Epub 2021 Apr 15.
Diabetic retinopathy is a multifactorial microvascular complication, and its pathogenesis hasn't been fully elucidated. The irreversible oxidation of cysteine 674 (C674) in the sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) was increased in the type 1 diabetic retinal vasculature. SERCA2 C674S knock-in (SKI) mouse line that half of C674 was replaced by serine 674 (S674) was used to study the effect of C674 inactivation on retinopathy. Compared with wild type (WT) mice, SKI mice had increased number of acellular capillaries and pericyte loss similar to those in type 1 diabetic WT mice. In the retina of SKI mice, pro-apoptotic proteins and intracellular Ca-dependent signaling pathways increased, while anti-apoptotic proteins and vessel density decreased. In endothelial cells, C674 inactivation increased the expression of pro-apoptotic proteins, damaged mitochondria, and induced cell apoptosis. These results suggest that a possible mechanism of retinopathy induced by type 1 diabetes is the interruption of calcium homeostasis in the retina by oxidation of C674. C674 is a key to maintain retinal health. Its inactivation can cause retinopathy similar to type 1 diabetes by promoting apoptosis. SERCA2 might be a potential target for the prevention and treatment of diabetic retinopathy.
糖尿病性视网膜病变是一种多因素的微血管并发症，其发病机制尚未完全阐明。1 型糖尿病视网膜血管中肌浆/内质网钙 ATP 酶 2（SERCA2）半胱氨酸 674（C674）的不可逆氧化增加。使用一半的 C674 被丝氨酸 674（S674）取代的 SERCA2 C674S 敲入（SKI）小鼠系来研究 C674 失活对视网膜病变的影响。与野生型（WT）小鼠相比，SKI 小鼠无细胞毛细血管数量增加，周细胞丢失，与 1 型糖尿病 WT 小鼠相似。在 SKI 小鼠的视网膜中，促凋亡蛋白和细胞内 Ca 依赖性信号通路增加，而抗凋亡蛋白和血管密度降低。在内皮细胞中，C674 失活增加了促凋亡蛋白的表达，破坏了线粒体，并诱导了细胞凋亡。这些结果表明，1 型糖尿病引起的视网膜病变的一个可能机制是 C674 氧化导致视网膜中钙稳态的中断。C674 是维持视网膜健康的关键。其失活可通过促进细胞凋亡引起类似于 1 型糖尿病的视网膜病变。SERCA2 可能是预防和治疗糖尿病性视网膜病变的潜在靶点。
