Vasomotor Dysfunction of Retinal Arterioles in Diabetes

视网膜病变是糖尿病的主要并发症，也是美国成年人失明的主要原因。 高血糖与早期糖尿病患者视网膜血流量减少有关，提示糖尿病患者视网膜功能障碍。 小动脉可能会对视网膜造成损害。有趣的是，视网膜血流的非侵入性成像 被认为是一扇通往心脏健康的“窗口”。尽管糖尿病会损害冠状动脉血流量 和促进心肌病，有可能是潜在的机制，目前尚不清楚，有助于 冠状动脉和视网膜小动脉功能障碍是不同的。此外，糖尿病动物模型的建立也与 用于视网膜和视网膜小动脉血管运动障碍的机制研究 心是缺的。为了解决这些临床上重要的问题，我们开发了链佐菌素诱导的1型 猪的糖尿病，我们已经展示的动物模型在视网膜血管运动方面与人类相似 监管/监管失调。我们的初步数据显示，在糖尿病的2周内，内皮依赖的一氧化氮 氧化物(NO)介导的视网膜和冠状小动脉的扩张受到特别的损害。内皮功能障碍 与氧化应激和增强的Rho激酶(ROCK)表达相关，并可以预防和 在冠状小动脉中恢复，但仅在视网膜小动脉中被抗氧化剂和精氨酸酶阻滞剂阻止。它 在短期糖尿病中，导致血管舒缩功能障碍的信号事件似乎是不同的。 急性(3小时)和持续(2-12周)高血糖状态下血管扩张功能障碍的机制差异 提示时间控制精氨酸酶II和SIRT1这两种没有生物利用度的调节酶可能会 在视网膜小动脉中介导这种病理生理过程，而c-jun氨基末端激酶的持续激活 (JNK)和精氨酸酶I参与冠状动脉功能障碍。然而，它的确切作用和信号序列 与氧化应激和精氨酸酶有关的特定岩石异构体激活还没有定义。在此，我们 将检验早期糖尿病激活内皮细胞依赖的JNK相互作用蛋白-1的假说 (JIP1)/JNK信号，增强下游NAD(P)H氧化酶和p38依赖的蛋白酶体 视网膜小动脉的活性和冠状小动脉的黄嘌呤氧化酶活性。氧化应激导致 时间控制精氨酸酶II和SIRT1，随后减少NO介导的视网膜扩张 而精氨酸酶I持续升高则维持冠状动脉功能不全。我们将追查3个 具体目标：(1)确定JIP1增强的岩石依赖性磷酸化是否有助于 糖尿病通过增加氧化应激导致视网膜和冠状动脉功能障碍。(二)确定 JNK依赖的氧化酶信号增强是否参与糖尿病引起的视网膜和视网膜功能障碍 冠状动脉小动脉。(3)确定精氨酸酶活性增强和p38诱导的细胞外信号转导通路是否激活 蛋白酶体有助于暂时控制糖尿病引起的视网膜和冠状动脉功能障碍。 结果将确定糖尿病早期视网膜和冠状小动脉功能障碍的新靶点。

Retinopathy is a major complication of diabetes mellitus and a leading cause of blindness in American adults. Hyperglycemia is associated with reduced retinal blood flow in early diabetes, suggesting that dysfunction of arterioles may contribute to retinal damage. Interestingly, noninvasive imaging of retinal blood flow is being regarded as providing a "window" into the health of the heart. Although diabetes can impair coronary blood flow and promote cardiomyopathy, it is possible that underlying mechanisms, which remain unclear, contributing to coronary and retinal arteriolar dysfunction are different. Also, development of a diabetes animal model relevant to human microcirculation for mechanistic study of vasomotor dysfunction of arterioles from the retina and heart is lacking. To address these clinically important issues, we developed streptozocin-induced type 1 diabetes in the pig, an animal model that we have shown resembles human in retinal vasomotor regulation/dysregulation. Our preliminary data show that within 2 wk of diabetes, endothelium-dependent nitric oxide (NO)-mediated dilation of retinal and coronary arterioles is specifically impaired. Endothelial dysfunction correlates with oxidative stress and enhanced Rho kinase (ROCK) expression, and can be prevented and restored in coronary arterioles but only prevented in retinal arterioles by antioxidants and arginase blockade. It appears that signaling events leading to their vasomotor dysfunction in short-term diabetes are different. Mechanistic differences in vasodilator dysfunction under acute (3 hr) vs. prolonged (2 to 12 wk) hyperglycemia suggest that temporal control of arginase II and SIRT1, two regulatory enzymes for NO bioavailability, may mediate this pathophysiology in retinal arterioles, whereas continuous activation of c-Jun N-terminal kinase (JNK) and arginase I contributes to coronary dysfunction. However, the exact role and signaling sequence for specific ROCK isoform activation linking to oxidative stress and arginase have not been defined. Herein, we will test the hypothesis that early diabetes activates endothelial ROCK-dependent JNK-interacting protein-1 (JIP1)/JNK signaling, which enhances downstream NAD(P)H oxidase and p38-dependent proteasome activities in retinal arterioles and xanthine oxidase activity in coronary arterioles. Oxidative stress leads to temporal control of arginase II and SIRT1 with subsequent reduction of NO-mediated dilation in retinal arterioles, whereas prolonged elevation of arginase I sustains coronary dysfunction. We will pursue 3 specific aims: (1) Determine whether enhanced ROCK-dependent phosphorylation of JIP1 contributes to diabetes-induced dysfunction of retinal and coronary arterioles by increasing oxidative stress. (2) Determine whether enhanced JNK-dependent oxidase signaling contributes to diabetes-induced dysfunction of retinal and coronary arterioles. (3) Determine whether enhanced arginase activity and p38-induced activation of proteasomes contribute to temporal control of diabetes-induced dysfunction of retinal and coronary arterioles. Outcomes will identify novel targets involved in retinal and coronary arteriolar dysfunction during early diabetes.