Angiogenesis induced by advanced glycation end products and its prevention by cerivastatin

Abstract

We previously have found that advanced glycation end products (AGE), senescent macroproteins formed at an accelerated rate in diabetes, arise in vivo not only from glucose but also from reducing sugars. Furthermore, we recently have shown that glyceraldehyde- and glycolaldehyde-derived AGE (glycer- and glycol-AGE) are mainly involved in loss of pericytes, the earliest histopathological hallmark of diabetic retinopathy. However, the effects of these AGE proteins on angiogenesis, another vascular derangement in diabetic retinopathy, remain to be elucidated. In this study, we investigated whether these AGE proteins elicit changes in cultured endothelial cells that are associated with angiogenesis. When human skin microvascular endothelial cells (EC) were cultured with glycer-AGE or glycol-AGE, growth and tube formation of EC, the key steps of angiogenesis, were significantly stimulated. The AGE-induced growth stimulation was significantly enhanced in AGE receptor (RAGE)-overexpressed EC. Furthermore, AGE increased transcriptional activity of nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) and then up-regulated mRNA levels of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) in EC. Cerivastatin, a hydroxymethylglutaryl CoA reductase inhibitor; pyrrolidinedithiocarbamate; or curcumin was found to completely prevent the AGE-induced increase in NF-kB and AP-1 activity, VEGF mRNA up-regulation, and the resultant increase in DNA synthesis in microvascular EC. These results suggest that the AGE-RAGE interaction elicited angiogenesis through the transcriptional activation of the VEGF gene via NF-kB and AP-1 factors. By blocking AGE-RAGE signaling pathways, cerivastatin might be a promising remedy for treating patients with proliferative diabetic retinopathy.

Vascular endothelial growth factor in eye disease

“…The beneficial effects of statin treatment in the diabetic retina were found to correlate with their ability to suppress redox-dependent activation of STAT3 (Al-Shabrawey et al, submitted). Statins have also been shown to inhibit angiotensin-induced activation of STAT3 in vitro (Horiuchi et al, 2003) and to prevent VEGF expression induced by advanced glycation end-products (Okamoto et al, 2002;Scalia and Stalker, 2002;Weis et al, 2002). These and other important therapeutic effects of statins are due not only to their lipid lowering ability, but also to their potent antioxidant and anti-inflammatory properties (Sowers, 2003).…”

Molecular mechanisms of Diabetic Retinopathy, general preventive strategies and novel therapeutic targets

“…Other observations in diabetic animals are compatible with a pathogenetic role for AGEs in microvascular disease. Similarly AGEs alone are given to achieve plasma concentrations equivalent to those seen in diabetic animals [47]. After 5 months, the renal AGE content in AGE-treated rats was 50% above that in controls, while the plasma concentration was 2.8 times greater than that of controls.…”

Mechanisms by which diabetes increases cardiovascular disease

“…Interestingly, acetylsalicylic acid -a drug widely use in patients suffering from atherosclerotic disease -and pentoxifyllin -a drug used in patients with peripheral artery disease -also inhibit non-enzymatic glycation [23]. Finally, the β-HMG CoA reductase inhibitor cerivastatin has been shown to inhibit AGE formation [24].…”