Zhi Li1, Jing Zhang1, Yanni Xue1, Ying He1, Lanlan Tang2, Min Ke3, Yan Gong4. 1. Department of Ophthalmology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430071, Hubei, China. 2. Department of Ophthalmology, Wuchang Hospital Affiliated to Wuhan University of Science and Technology, Wuhan, China. 3. Department of Ophthalmology, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430071, Hubei, China. keminyk@163.com. 4. Department of Biological Repositories, Zhongnan Hospital of Wuhan University, 169 Donghu Road, Wuhan, 430071, Hubei, China. yan.gong@whu.edu.cn.
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.
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.
Authors: Ronald A Markle; Jihong Han; Barbara D Summers; Toru Yokoyama; Katherine A Hajjar; David P Hajjar; Antonio M Gotto; Andrew C Nicholson Journal: J Cell Biochem Date: 2003-09-01 Impact factor: 4.429
Authors: Arpita S Bharadwaj; Binoy Appukuttan; Phillip A Wilmarth; Yuzhen Pan; Andrew J Stempel; Timothy J Chipps; Eric E Benedetti; David O Zamora; Dongseok Choi; Larry L David; Justine R Smith Journal: Prog Retin Eye Res Date: 2012-09-11 Impact factor: 21.198