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Telmisartan, PPAR-g and Retinal Neovascularization
Author Response: Telmisartan, PPAR-g and Retinal Neovascularization
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Harrihar A. Pershadsingh
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hpershad{at}UCI.edu Harrihar A. Pershadsingh
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Nagai et al.1 have shown that the selective angiotensin II (AII) type 1 receptor (AT1-R) antagonist, telmisartan has anti-inflammatory and anti-angiogenic effects on pathologic, but not physiologic retinal neovascularization. They conclude that this effect was specifically related the selective blockade by telmisartan of the pro-inflammatory AII-dependent signaling pathway,2 a major pathological determinant of retinal neovascularization.1 Telmisartan has recently been shown to activate the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPARg), a major regulator of lipid and glucose metabolism and pharmacological target for treating type 2 diabetes.3,4 Ligand-dependent activation of PPARg has been shown to inhibit mitogen and growth factor-induced vascular smooth muscle cell proliferation, infiltration of the arterial wall by macrophages and activated T lymphocytes. PPARg activation suppresses the production of inflammatory molecules including inflammatory interleukins, tumor necrosis factor-F, adhesion molecules and matrix metalloproteinases by monocyte/macrophages and activated T lymphocytes, and inducible nitric oxide synthase by endothelial cells.5,6 This could be of major relevance to retinal neovascularization. The anti-diabetic thiazolidinediones (TZDs) are PPARg agonists that have potent anti-proliferative effects by suppressing cell growth and migration mediated by mitogenic growth factors, including vascular endothelial growth factor (VEGF).6-8 PPARg is expressed in various tissues of the mammalian eye,9 including human retinal pigment epithelial cells,7,8 bovine choroidal endothelial cells7 and rat corneal epithelium and endothelium.9,10 The anti-diabetic thiazolidinediones (TZDs) rosiglitazone and troglitazone, high affinity PPARg agonists, have been shown to inhibit VEGF-induced retinal endothelial cell proliferation, migration, tube formation, and signaling, in vitro.7,8 Specific TZDs have also been shown to inhibit laser-induced choroidal,7 hypoxia-induced retinal,8 and VEGF-induced corneal10 angiogenesis and neovascularization in rodents, in vivo. There is little doubt that, by triggering the AT1-R-dependent pro-inflammatory cascade, AII is a mediator of VEGF-induced retinal inflammation, angiogenesis and neovascularization [see ref. 1 for discussion], and that AT1-R blockade is an palliative maneuver. However, based on data with the TZDs, it is now evident that PPARg activation constitutes a complimentary pathway for suppressing inflammatory and proliferative retinopathy. Thus telmisartan may mediate anti-inflammatory effects via both pathways.3,4 Indeed, in type 2 diabetic patients, both rosiglitazone11 and telmisartan12 were shown to reduce the serum concentration of highly sensitive Creactive protein, a cardiovascular risk factor and marker of systemic inflammation in humans. In sum, the fact that telmisartan, in addition to blocking the AT1-R, also activates PPARg, implies that the inhibitory effect of telmisartan on pathological neovascularization is likely related to its ability to both block the AT1-R and activate PPARg. Future studies on the role of each of these anti-inflammatory mechanisms are required to determine their respective contributions to preventing the pathogenesis of neovascular proliferative retinopathies and maculopathies. Suppressing inflammatory processes by simultaneously regulating these two pathways may constitute an advance in the treatment of inflammatory, proliferative diseases of the eye. In this regard, telmisartan appears a suitable agent to test this hypothesis. Harrihar A. Pershadsingh CR: I,P References 1. Nagai N, Noda K, Urano T, et al. Selective
suppression of pathologic, but not physiologic, retinal neovascularization by blocking the angiotensin II type 1 receptor. Invest Ophthalmol Vis Sci. 2005;46:1078-1084. |
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Susumu Ishida
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ishidasu{at}sc.itc.keio.ac.jp Susumu Ishida
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We thank Pershadsingh for his comments and appreciate the opportunity to respond. Our data have shown that telmisartan, an AT1-R blocker (ARB), had an inhibitory effect on pathological neovascularization in a murine model of ischemic retinopathy through the suppression of ICAM-1-mediated inflammatory cell adhesion to the retinal vessels.1 The renin-angiotensin system, an important controller of systemic blood pressure, has recently been reported to play a role in multiple biological phenomena including neovascularization and inflammation. AT1-R signaling blockade with an ARB candesartan or genetically altered mice led to reduction of neovascularization and inflammation in tumor models.2,3 These recent findings suggest the potential use of ARBs as a novel therapeutic agent for pathological neovascularization in the eye. In addition to the AT1-R-blocking function, telmisartan has PPAR-g-stimulating activity, which has recently been noticed as a specific property lacking in other ARBs.4,5 PPAR, a transcription factor that belongs to the nuclear receptor superfamily, has multiple bioactivities including the regulation of gene expression related to the metabolism of glucose and lipid. As concerns angiogenesis, application of PPAR-g ligands caused the suppression of VEGF-induced corneal neovascularization6 and laser-induced choroidal neovascularization.7 Also, PPAR-g signaling was shown to inhibit inflammatory processes including leukocyte infiltration and cytokine expression.8,9 Accordingly, AT1-R blockade and PPAR-g activation, both of which telmisartan induces, are likely to share multiple bioactivities including the suppression of neovascularization and inflammation. We have already obtained the new data showing that valsaratan, an ARB which lacks PPAR-g-stimulating activity, reduced choroidal neovascularization as well as telmisartan did (in revision). The data further confirm the suppressive effect of ARBs, independently of PPAR-g, on ocular neovascularization and inflammation. Additionally, we have newly obtained significant findings through our animal experiments to examine whether or not telmisartan functions as a PPAR-g stimulator to reduce ocular neovascularization (in revision). Multiple roles of PPAR-g signaling in various ocular pathologies are currently under investigation. Norihiro Nagai,1,2,3 Yuichi Oike,1,3 and Susumu Ishida1,2 The 1Laboratory of Retinal Cell Biology and the Departments of 2Ophthalmology and 3Cell Differentiation, Keio University School of Medicine, Tokyo, Japan References 1. Nagai N, Noda K, Urano T, et al. Selective suppression of pathological, but not physiological, retinal neovascularization by blocking angiotensin II type 1 receptor. Invest Ophthalmol Vis Sci. 2005;46:1078-1084. |
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