Endocrine Abstracts

Introduction: In the presence of atherogenic plaque, estrogens may be potentially harmful. Among the key vessel wall components in the later stages of atherogenic process are endothelial cells (ECs). During the stages of plaque instability/rupture, metalloproteinases (MMP2 and MMP9), their inhibitors (TIMP2 and TIMP1), RANK, RANKL, OPG, MCP1, lysyl oxidase (LOX), PDGF, and ADAMTS4 play critical role. We aimed to investigate i) the effect of oestrogens on the expression of the above molecules in ECs and ii) which type of estrogen receptor mediates these effects.

Methods: Human aortic endothelial cells (HAECs) were cultured, in the absence or in the presence of estradiol (E₂) at various concentrations and for various incubation times without or with pre-incubation with TNFα (resembling a low grade inflammation state). The mRNA expression of all the aforementioned genes was assessed by real-time PCR. Zymography for MMP2 and MMP9 activity was also performed. The experiments were repeated in either ERα- or ERβ-transfected HAECs.

Results: HAECs did not express ERα and ERβ while they express G-protein coupled estrogen receptor 30 (GPR30). Incubation with E₂ at low concentrations induced an increase in LOX and MCP1 mRNA expression. Zymography revealed that E₂ induced a down regulation of active MMP2, dose-dependently. Incubation with E₂ following pretreatment with TNFα induced a marginal increase in MMP9 and TIMP1 expression and a ten times increase in MCP1, dose-dependently. In ERα-transfected HAECs, incubation with E₂ led to upregulation of TIMP1 and TIMP2 and in marginal increase of LOX and MCP1. E₂ increased the expression of MCP1 and LOX while decreased the expression of PDGF in ERβ-transfected HAECs.

Conclusion: E₂ induced different effects regarding atherogenic plaque instability through different ERs. The balance of expression of the various ER subtypes may play an important role in the paradoxical characterization of estrogens as both beneficial and harmful.

Disclosure: General Secretariat for Research and Technology.