Abstract
Decreased production and/or impaired action of nitric oxide (NO) play a role in the pathogenesis of atherosclerotic cardiovascular disease and erectile dysfunction (ED) in diabetic patients. Under hyperglycemic conditions, formation and accumulation of advanced glycation end products (AGE) have been known to progress, thus contributing to tissue damage in diabetes. However, effects of inhibitors of phosphodiesterase-5 (PDE-5), an enzyme that catalyzes the degradation of cyclic guanosin-monophosphate (cGMP) and subsequently blocks the actions of NO, on AGE-exposed endothelial cells remain unknown. Therefore, this study investigated whether and how vardenafil, an inhibitor of PDE-5, could block the deleterious effects of AGE on human umbilical vein endothelial cells (HUVEC). Gene and protein expression was analyzed in quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) and western blots, respectively. Intracellular formation of reactive oxygen species (ROS) was evaluated with dihydroethidium staining. AGE increased receptor for AGE (RAGE) mRNA and protein levels in HUVEC, both of which were significantly inhibited by the treatments with 30 nM vardenafil or 5 μM 8-Br-cGMP, an analogue of cGMP. Further, vardenafil reduced the AGE-induced ROS generation and subsequently inhibited up-regulation of monocyte chemoattractant protein-1 (MCP-1) mRNA levels in HUVEC. We demonstrated here for the first time that vardenafil could block the AGE-induced up-regulation of MCP-1 mRNA levels in HUVEC by suppressing RAGE expression and subsequent ROS generation via elevation of cGMP. Our present results suggest that vardenafil directly acts on endothelial cells and it could work as an anti-inflammatory agent against AGE.
References
Lin CS (2009) Phosphodiesterase type 5 regulation in the penile corpora cavernosa. J Sex Med Suppl 3:203–209
Gur S, Sikka SC, Hellstrom WJ (2008) Novel phosphodiesterase-5 (PDE5) inhibitors in the alleviation of erectile dysfunction due to diabetes and ageing-induced oxidative stress. Expert Opin Investig Drugs 17:855–864
Gazzaruso C, Solerte SB, Pujia A, Coppola A, Vezzoli M, Salvucci F, Valenti C, Giustina A, Garzaniti A (2008) Erectile dysfunction as a predictor of cardiovascular events and death in diabetic patients with angiographically proven asymptomatic coronary artery disease: a potential protective role for statins and 5-phosphodiesterase inhibitors. J Am Coll Cardiol 51:2040–2044
Speel TG, van Langen H, Meuleman EJ (2003) The risk of coronary heart disease in men with erectile dysfunction. Eur Urol 44:366–370
Yamagishi S, Nakamura K, Matsui T (2008) Role of oxidative stress in the development of vascular injury and its therapeutic intervention by nifedipine. Curr Med Chem 15:172–177
Yamagishi S, Imaizumi T (2005) Diabetic vascular complications: pathophysiology, biochemical basis and potential therapeutic strategy. Curr Pharm Des 11:2279–2299
Bierhaus A, Stern DM, Nawroth PP (2006) RAGE in inflammation: a new therapeutic target? Curr Opin Investig Drugs 7:985–991
Yamagishi S, Matsui T, Nakamura K (2007) Kinetics, role and therapeutic implications of endogenous soluble form of receptor for advanced glycation end products (sRAGE) in diabetes. Curr Drug Targets 8:1138–1143
Yoshida T, Yamagishi S, Nakamura K, Matsui T, Imaizumi T, Takeuchi M, Koga H, Ueno T, Sata M (2006) Telmisartan inhibits AGE-induced C-reactive protein production through downregulation of the receptor for AGE via peroxisome proliferator-activated receptor-gamma activation. Diabetologia 49:3094–3099
Usta MF, Kendirci M, Gur S, Foxwell NA, Bivalacqua TJ, Cellek S, Hellstrom WJG (2006) The breakdown of preformed advanced glycation end products reverses erectile dysfunction in streptozotocin-induced diabetic rats: preventive versus curative treatment. J Sex Med 3:242–252
Rajagopalan P, Mazzu A, Xia C, Dawkins R, Sundaresan P (2003) Effect of high-fat breakfast and moderate-fat evening meal on the pharmacokinetics of vardenafil, an oral phosphodiesterase-5 inhibitor for the treatment of erectile dysfunction. J Clin Pharmacol 43:260–267
Acknowledgments
This work was supported in part by Grants of Collaboration with Venture Companies Project from the Ministry of Education, Culture, Sports, Science and Technology, Japan (S.Y.).
Conflict of interest
None.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ishibashi, Y., Matsui, T., Takeuchi, M. et al. Vardenafil, an inhibitor of phosphodiesterase-5, blocks advanced glycation end product (AGE)-induced up-regulation of monocyte chemoattractant protein-1 mRNA levels in endothelial cells by suppressing AGE receptor (RAGE) expression via elevation of cGMP. Clin Exp Med 11, 131–135 (2011). https://doi.org/10.1007/s10238-010-0109-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10238-010-0109-2