Diabetes and Age-Related Reactive Dicarbonyls Cause Endothelial Cell Dysfunction

K. Jacobs; B. Hofmann; R.-E Silber; H. Treede; A. Simm; A. Navarrete Santos

doi:10.1055/s-0036-1571716

The Thoracic and Cardiovascular Surgeon, Table of Contents

Diabetes and Age-Related Reactive Dicarbonyls Cause Endothelial Cell Dysfunction

K. Jacobs ¹, B. Hofmann ¹, R.-E Silber ¹, H. Treede ¹, A. Simm ¹, A. Navarrete Santos ¹

¹Department of Cardiac Surgery, University Hospital Halle (Saale), Halle (Saale), Germany

Abstract

Objectives: Advanced Glycation End products (AGEs) as well as AGE inducing dicarbonyls are involved in cardiovascular aging. Circulating AGEs and dicarbonyls like Glyoxal (GO) and Methylglyoxal (MGO) are directly in contact with endothelial cells (ECs) and are able to modulate fetal EC properties. In contrast, little is known about the interaction with primary ECs isolated from the vessels of elderly patients.

Methods: Primary culture ECs were isolated by enzymatic digestion from residual bypass graft material (HSVECs, human saphenous vein endothelial cells) of coronary heart disease patients. HSVECs were stimulated with different concentrations of low and high in vivo modified BSA, GO and MGO. The cells were chronically stimulated 3–4 days and then analyzed according to various functional parameters.

Results: Our preliminary results show that GO leads to morphological - age associated -changes in HSVECs. MGO alone has no effect, only in combination with GO further morphological changes of HSVECs were induced. On the molecular level, GO in combination with MGO induce cellular senescence, demonstrated by increased p21 protein expression and senescence-associated β-galactosidase activity. Both dicarbonyls decreased mRNA expression of cell-adhesion molecules and affect the expression of different receptors for AGEs (RAGE ↑; SR-AII ↑; AGE-R complex ↓; SR-AI ↓; FEEL-1 ↓). In addition, the permeability of HSVEC monolayer decreased after chronic treatment with GO/MGO or with high in vivo-modified BSA.

Conclusion: Our findings suggest that elevated levels of diabetes / age related dicarbonyls and AGEs can damage the endothelium and thus promote the development of vascular dysfunction. The elucidation of the mechanism by which GO/MGO act is ongoing.