Abstract
Diabetes and its vascular complications affect an increasing number of people. This disease of epidemic proportion nowadays involves abnormalities of large and small blood vessels, all commencing with alterations of the endothelial cell (EC) functions. Cardiovascular diseases are a major cause of death and disability among diabetic patients. In diabetes, EC dysfunction (ECD) is induced by the pathological increase of glucose and by the appearance of advanced glycation end products (AGE) attached to the plasma proteins, including lipoproteins. AGE proteins interact with their specific receptors on EC plasma membrane promoting activation of signaling pathways, resulting in decreased nitric oxide bioavailability, increased intracellular oxidative and inflammatory stress, causing dysfunction and finally apoptosis of EC. Irreversibly glycated lipoproteins (AGE-Lp) were proven to have an important role in accelerating atherosclerosis in diabetes. The aim of the present review is to present up-to-date information connecting hyperglycemia, ECD and two classes of glycated Lp, glycated low-density lipoproteins and glycated high-density lipoproteins, which contribute to the aggravation of diabetes complications. We will highlight the role of dyslipidemia, oxidative and inflammatory stress and epigenetic risk factors, along with the specific mechanisms connecting them, as well as the new promising therapies to alleviate ECD in diabetes.
Highlights
The prevalence of diabetes mellitus (DM) is rapidly increasing worldwide [1]
Accelerated atherosclerosis represents a major complication of the macro-vasculature of diabetic patients that can cause major acute cardiovascular events
Alterations in lipid metabolism are at the core of type 2 DM (T2DM) phenotypes and probably greatly contribute to the increased risk of cardiovascular disease associated with diabetes
Summary
The prevalence of diabetes mellitus (DM) is rapidly increasing worldwide [1]. The decreased quality of life of diabetic patients and the social and economic burden of this disease emphasize the need to establish the causative mechanisms of DM that will allow the identification of new therapies to cure diabetes and its associated vascular complications. Large-scale clinical studies have shown that despite good glycemic control, the vascular complications persist and even evolve [3,4]. This phenomenon is known as the “metabolic memory” of the cells [5]. It favors an increased trans-endothelial transport of plasma proteins and lipoproteins (Lp), stimulates the adhesion and sub-endothelial transmigration of blood monocytes, supports the migration and proliferation of vascular smooth muscle cells (SMC) from the media to the intima and impedes the fibrinolytic processes, increasing the risk of cardiovascular events in diabetic patients [10]. Special attention is given to the interaction of EC with glycated low-density lipoproteins (gLDL) and glycated high-density lipoproteins (gHDL) as important players in the accelerated-atherosclerotic process in diabetes
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