Homocysteinylation of low-density lipoproteins (LDL) from subjects with type 1 diabetes and human aortic endothelial cells: An in vitro study

Arianna Vignini, Laura Nanetti, Francesca Raffaelli, Tiziana Bacchetti, Gianna Ferretti, Rosa Anna Rabini, Eleonora Salvolini, Laura Mazzanti

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Type 1 (T1D) and Type 2 (T2D) diabetes are independent risk factors for cardiovascular disease (CVD), stroke and coronary artery disease. The higher risk of CVD associated with diabetes has been related to hyperglycaemia, hyperinsulinaemia and to alterations of the levels and/or heterogeneity of the major lipoprotein classes. An increase of small and dense low-density lipoproteins (LDL) and of glycated apoproteins has been described in patients with diabetes. These compositional and physicochemical changes reflect alterations in the susceptibility to lipid peroxidation and impaired interactions with cell receptors. In the past decade, homocysteine (Hcy) has been recognized as a risk factor for cardiovascular disease. Several studies have observed a relationship between Hcy levels and chronic complications of diabetes, and it has been reported that hyperhomocysteinaemia is associated with coronary heart disease in diabetes. The mechanisms by which hyperhomocysteinaemia may be involved in the development of atherogenesis are only partially understood, but induction of oxidative damage and endothelial injury have been suggested. It has been demonstrated that Hcy-induced vascular damage could be related to homocysteine-thiolactone (Hcy-thiolactone), an Hcy reactive product formed in human cells from the enzymatic conversion of homocysteine to the corresponding thioester. The interaction between LDL and Hcy-thiolactone induces the formation of homocystamide-LDL adducts (Hcy-LDL). Homocysteinylation of lipoproteins is accompanied by structural and functional alterations and it has been suggested that homocysteinylation could increase the atherogenicity of lipoproteins and contribute to abnormal interactions with cells. The aim of this study is to further investigate the role of homocysteinylation of LDL in the pathogenesis of diabetic vascular complications. We compared the effect of homocysteinylation of LDL isolated from healthy subjects or T1D patients in good metabolic control on NO production, intracellular Ca2+ concentration [Ca2+]i and Na+/K+-ATPase activity from human aortic endothelial cells (HAEC) in culture. In fact, in a previous study, we demonstrated that a short term interaction with LDL from Type 1 diabetic patients causes alterations of the plasma membrane surface and of cellular functions in endothelial cells in a possibly atherogenic way. In the present work, we showed that [Ca2+]i from HAEC incubated with Hcy-LDL from diabetic patients was greater than after incubation with Hcy-LDL from control subjects and untreated LDL from diabetic patients (P+/K+-ATPase activity had an opposite trend. These results show that the compositional changes in Hcy-LDL from diabetic subjects have cytotoxic effects on human endothelial cells. Therefore, we suggest that the higher oxidative damage exerted by LDL from diabetic patients on endothelial cells could contribute to the high risk of cardiovascular disease associated with Type 1 diabetes.

Original languageEnglish
Title of host publicationHandbook of Lipoprotein Research
PublisherNova Science Publishers, Inc
Pages183-193
Number of pages11
ISBN (Print)9781616681869
Publication statusPublished - Jan 2011

Keywords

  • [Ca]i
  • Homocysteine
  • LDL
  • Na/K-atpase activity
  • Nitric oxide
  • Type 1 diabetes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Vignini, A., Nanetti, L., Raffaelli, F., Bacchetti, T., Ferretti, G., Rabini, R. A., Salvolini, E., & Mazzanti, L. (2011). Homocysteinylation of low-density lipoproteins (LDL) from subjects with type 1 diabetes and human aortic endothelial cells: An in vitro study. In Handbook of Lipoprotein Research (pp. 183-193). Nova Science Publishers, Inc.