培伐他汀通过 HMG-CoA 还原酶非依赖性激活 RhoA 介导的途径和黏着斑刺激视网膜血管生成。

Pitavastatin stimulates retinal angiogenesis via HMG-CoA reductase-independent activation of RhoA-mediated pathways and focal adhesion.

机构信息

Department of Ophthalmology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430071, Hubei, China.

Department of Ophthalmology, Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China.

出版信息

Graefes Arch Clin Exp Ophthalmol. 2021 Sep;259(9):2707-2716. doi: 10.1007/s00417-021-05328-4. Epub 2021 Jul 30.

DOI:10.1007/s00417-021-05328-4

PMID:34328550

Abstract

BACKGROUND

Excessive angiogenesis of the retina is a key component of irreversible causes of blindness in many ocular diseases. Pitavastatin is a cholesterol-lowering drug used to reduce the risk of cardiovascular diseases. Various studies have shown the effects of pitavastatin on angiogenesis but the conclusions are contradictory. The effects of pitavastatin on retinal angiogenesis have not been revealed. This study investigated the effects of pitavastatin at clinically relevant concentrations on retinal angiogenesis and its underlying mechanisms using retinal microvascular endothelial cells (RMECs).

METHODS

The effects of pitavastatin on retinal angiogenesis were determined using in vitro model of retinal angiogenesis, endothelial cell migration, adhesion, proliferation, and apoptosis assays. The mechanism studies were conducted using immunoblotting and stress fiber staining.

RESULTS

Pitavastatin stimulated capillary network formation of RMECs in a similar manner as vascular endothelial growth factor (VEGF) and lipopolysaccharide (LPS). Pitavastatin also increased RMEC migration, adhesion to Matrigel, growth, and survival. The combination of pitavastatin with VEGF or LPS was more effective than VEGF or LPS alone in stimulating biological activities of RMECs, suggesting that pitavastatin can enhance the stimulatory effects of VEGF and LPS on retinal angiogenesis. Pitavastatin acted on RMECs in a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase-independent manner. In contrast, pitavastatin activated pro-angiogenic microenvironment via promoting the secretion of VEGF and stimulated retinal angiogenesis via multiple mechanisms including activation of RhoA-mediated pathways, induction of focal adhesion complex formation, and activation of ERK pathway.

CONCLUSION

Our work provides a preclinical evidence on the pro-angiogenic effect of pitavastatin in retina via multiple mechanisms that are irrelevant to mevalonate pathway.

摘要

背景

视网膜过度血管生成是许多眼部疾病导致不可逆转失明的关键因素。匹伐他汀是一种降胆固醇药物，用于降低心血管疾病的风险。各种研究表明匹伐他汀对血管生成有影响，但结论相互矛盾。匹伐他汀对视网膜血管生成的影响尚未揭示。本研究使用视网膜微血管内皮细胞（RMEC）研究了临床相关浓度的匹伐他汀对视网膜血管生成及其潜在机制的影响。

方法

使用视网膜血管生成的体外模型、内皮细胞迁移、黏附、增殖和凋亡测定来确定匹伐他汀对视网膜血管生成的影响。使用免疫印迹和应激纤维染色进行机制研究。

结果

匹伐他汀以类似于血管内皮生长因子（VEGF）和脂多糖（LPS）的方式刺激 RMEC 的毛细血管网络形成。匹伐他汀还增加了 RMEC 的迁移、黏附到 Matrigel、生长和存活。匹伐他汀与 VEGF 或 LPS 的组合比 VEGF 或 LPS 单独刺激 RMEC 的生物学活性更有效，表明匹伐他汀可以增强 VEGF 和 LPS 对视网膜血管生成的刺激作用。匹伐他汀以 3-羟-3-甲基戊二酰辅酶 A（HMG-CoA）还原酶非依赖性方式作用于 RMEC。相比之下，匹伐他汀通过促进 VEGF 的分泌来发挥促血管生成的微环境作用，并通过多种机制刺激视网膜血管生成，包括激活 RhoA 介导的途径、诱导焦点黏附复合物形成以及激活 ERK 途径。