Molecular and Cellular Mechanisms of Electronegative Lipoproteins in Cardiovascular Diseases

Abstract

Dysregulation of glucose and lipid metabolism increases plasma levels of lipoproteins and triglycerides, resulting in vascular endothelial damage. Remarkably, the oxidation of lipid and lipoprotein particles generates electronegative lipoproteins that mediate cellular deterioration of atherosclerosis. In this review, we examined the core of atherosclerotic plaque, which is enriched by byproducts of lipid metabolism and lipoproteins, such as oxidized low-density lipoproteins (oxLDL) and electronegative subfraction of LDL (LDL(−)). We also summarized the chemical properties, receptors, and molecular mechanisms of LDL(−). In combination with other well-known markers of inflammation, namely metabolic diseases, we concluded that LDL(−) can be used as a novel prognostic tool for these lipid disorders. In addition, through understanding the underlying pathophysiological molecular routes for endothelial dysfunction and inflammation, we may reassess current therapeutics and might gain a new direction to treat atherosclerotic cardiovascular diseases, mainly targeting LDL(−) clearance.

The Impaired Bioenergetics of Diabetic Cardiac Microvascular Endothelial Cells

“…Diabetic patients have elevated plasma levels of lipoproteins and triglycerides, which can cause vascular endothelial damage (6,6). Additionally, sustained hyperglycemia associated with increased oxidative stress impairs endothelial cell replication and accelerates endothelial cell apoptosis via mitochondrial dysfunction in both type 1 and type 2 diabetes (7)(8)(9).…”

Circulating Biomarkers Reflecting Destabilization Mechanisms of Coronary Artery Plaques: Are We Looking for the Impossible?

“…Hence, since major CV events arise from vulnerable plaques, it is reasonable to infer that lipid status could indicate plaque vulnerability. Unlike in plasma, where LDL can be scarcely modified, in the atherosclerotic plaque, LDL is easily modified under the effect of free radicals and enzymatic activity [107]. More importantly, these modified LDLs gain inflammatory properties and become aggregated, impeding their return to the circulation [103,108].…”

Autoimmune Rheumatic Diseases: An Update on the Role of Atherogenic Electronegative LDL and Potential Therapeutic Strategies

“…An important scavenger receptor, LOX-1 exhibits binding activity for multiple ligands, including oxidized LDL (ox-LDL), polyanionic chemicals, anionic phospholipids, cellular ligands (apoptotic/aged cells, activated platelets, and bacteria), and bile salt-dependent lipase [ 92 , 93 ]. After being internalized via LOX-1, L5 exerts its signaling in vascular ECs and monocytes [ 50 , 51 , 52 , 53 , 54 , 84 , 90 ].…”

“…L5 and LDL (−) are not recognized by the normal LDL receptor (LDLR) because of their electronegativity; rather, they signal through lectin-like oxidized LDL receptor 1 (LOX-1) to induce a broad spectrum of inflammatory reactions in adipose tissue [ 50 ] and vascular cells [ 51 ], as well as endothelial cell (EC) dysfunction and inflammation [ 52 ]. Accordingly, both L5 and LDL (−) stimulate inflammasome formation, which involves the participation and release of several cytokines, including interleukin 1β (IL-1β), IL-6, and IL-18 [ 51 , 53 , 54 ].…”