Bazedoxifene blocks AGEs-RAGE-induced superoxide generation and MCP-1 level in endothelial cells

Abstract

Advanced glycation endproducts (AGEs) and their receptor (RAGE) play a role in vascular complications in diabetes. We have previously shown that 17β-estradiol at 10 nmol/l, a nearly identical plasma concentration to that during mid-pregnancy, up-regulates RAGE expression in endothelial cells. The finding might suggest the involvement of 17β-estradiol in the deterioration of vascular complications in diabetes during pregnancy. However, the effects of the selective estrogen receptor modulator, bazedoxifene, on oxidative and inflammatory reactions in AGEs-exposed endothelial cells remain unknown. In this study, we addressed the issue. Ten nmol/l 17β-estradiol increased RAGE and monocyte chemoattractant protein-1 (MCP-1) gene and protein expression in human umbilical vein endothelial cells (HUVECs), both of which were blocked by 10 nmol/l bazedoxifene. Bazedoxifene at 10 nmol/l also significantly inhibited the AGEs-induced superoxide generation, RAGE and MCP-1 gene and protein expression in HUVECs. The present study suggests that blockade of the AGEs–RAGE axis by bazedoxifene might be a novel therapeutic target for preventing vascular damage in diabetes, especially in postmenopausal women.

Key words::

• AGEs
• BAZEDOXIFENE
• CARDIOVASCULAR DISEASE
• OXIDATIVE STRESS
• RAGE
• SERM

Conflict of interest Dr Ueda, Dr Fukami, Dr Okuda, Dr Ohta and Dr Yamagishi have received honoraria such as lecture fees from Pfizer.

Source of funding This study was supported in part by Grants-in-Aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science and Technology, Japan (to S.Y.), and by MEXT-Supported Program for the Strategic Research Foundation at Private Universities, the Ministry of Education, Culture, Sports, Science and Technology (MEXT) (to S.Y.).