Dysfunctional HDL and atherosclerotic cardiovascular disease

Abstract

High-density lipoproteins (HDLs) protect against atherosclerosis by removing excess cholesterol from macrophages through the ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) pathways involved in reverse cholesterol transport. Factors that impair the availability of functional apolipoproteins or the activities of ABCA1 and ABCG1 could, therefore, strongly influence atherogenesis. HDL also inhibits lipid oxidation, restores endothelial function, exerts anti-inflammatory and antiapoptotic actions, and exerts anti-inflammatory actions in animal models. Such properties could contribute considerably to the capacity of HDL to inhibit atherosclerosis. Systemic and vascular inflammation has been proposed to convert HDL to a dysfunctional form that has impaired antiatherogenic effects. A loss of anti-inflammatory and antioxidative proteins, perhaps in combination with a gain of proinflammatory proteins, might be another important component in rendering HDL dysfunctional. The proinflammatory enzyme myeloperoxidase induces both oxidative modification and nitrosylation of specific residues on plasma and arterial apolipoprotein A-I to render HDL dysfunctional, which results in impaired ABCA1 macrophage transport, the activation of inflammatory pathways, and an increased risk of coronary artery disease. Understanding the features of dysfunctional HDL or apolipoprotein A-I in clinical practice might lead to new diagnostic and therapeutic approaches to atherosclerosis.

ApoA1 and ApoA1-specific self-antibodies in cardiovascular disease

“…ApoA1 exposed to cyanate (HOCN), a product of HOSCN decomposition, lack the ability to control RCT and become pro-inflammatory. 80,81 Compared with native HDL, in ApoE-deficient mice, MPOmodified HDL lose anti-atherogenic properties as they unable to stabilize plaque, prevent foam cell formation, and suppress formation of macrophages with the pro-inflammatory phenotype. 34 MPO-modified HDL cannot bind to the HDL receptor and scavenger receptor B1, and promote proinflammatory activities such as upregulation of nuclear factor (NF)-κB and expression of adhesion molecules by ECs.…”

Dual Actions of Apolipoprotein A-I on Glucose-Stimulated Insulin Secretion and Insulin-Independent Peripheral Tissue Glucose Uptake Lead to Increased Heart and Skeletal Muscle Glucose Disposal

“…Other beneficial effects of apoA-I on CVD risk include its anti-inflammatory and antioxidative functions (reviewed in Rosenson et al [4]). In recent years, apoA-I has also been ascribed a glucose-controlling function, and studies show that apoA-I/HDL induces glucose uptake in cultured muscle myotubes (5-7) and stimulates insulin secretion from cultured b-cells (8).…”

microRNAs in lipoprotein and lipid metabolism: from biological function to clinical application

“…Interestingly, the intracellular miRNA levels were decreased in PBMCs after incubation with HDLs from healthy subjects, whereas they were increased after incubation with HDLs from CAD and ACS patients [7]. This differential cellular response to HDLs from healthy and diseased subjects may reflect physiological changes in HDL functions [150]. The analysis of intracellular pri-miRNA and pre-miRNA levels revealed that the observed changes in PBMCs might be due to transcriptional changes in miR-126-3p, but not miR-223-3p and miR92a-3p [7], raising the interesting hypothesis that PBMCs may export miRNAs to HDLs.…”