BACKGROUND:Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of the LDL receptor (LDLr) in hepatocytes, and its expression in mouse liver has been shown to decrease with fenofibrate treatment.
Objective-To determine if niacin can confer cardiovascular benefit by inhibiting vascular inflammation and improving endothelial function independent of changes in plasma lipid and lipoprotein levels. Methods and Results-New Zealand white rabbits received normal chow or chow supplemented with 0.6% or 1.2%(wt/wt) niacin. This regimen had no effect on plasma cholesterol, triglyceride, or high-density lipoprotein levels. Acute vascular inflammation and endothelial dysfunction were induced in the animals with a periarterial carotid collar. At the 24-hour postcollar implantation, the endothelial expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and monocyte chemotactic protein-1 was markedly decreased in the niacin-supplemented animals compared with controls. Niacin also inhibited intima-media neutrophil recruitment and myeloperoxidase accumulation, enhanced endothelial-dependent vasorelaxation and cyclic guanosine monophosphate production, increased vascular reduced glutathione content, and protected against hypochlorous acid-induced endothelial dysfunction and tumor necrosis factor ␣-induced vascular inflammation.
Conclusion-Previous human intervention studies have demonstrated that niacin inhibits coronary artery disease. Thisbenefit is thought to be because of its ability to reduce low-density lipoprotein and plasma triglyceride levels and increase high-density lipoprotein levels. The present study showed that niacin inhibits vascular inflammation and protects against endothelial dysfunction independent of these changes in plasma lipid levels. Key Words: niacin Ⅲ inflammation Ⅲ endothelial dysfunction N iacin (nicotinic acid) has been used for more than 30 years to treat plasma lipid disorders and to prevent atherosclerotic cardiovascular disease. 1 At pharmacological doses, niacin reduces low-density lipoprotein cholesterol, plasma triglyceride, nonesterified fatty acid, and lipoprotein(a) levels. Niacin also increases the concentration of high-density lipoproteins (HDLs). 2 Human intervention studies have indicated that treatment with niacin, either alone or in combination with other lipid-lowering agents, can slow or reverse the progression of atherosclerosis and reduce cardiovascular event rates and total mortality in patients with hypercholesterolemia and established atherosclerotic cardiovascular disease. 2 In combination therapy with statins, niacin reduces cardiovascular events 3 and slows coronary atherosclerosis progression. 4 It also reduces coronary stenosis progression in patients with metabolic syndrome. 5 It has always been assumed that these beneficial effects are the result of the lipid-modifying effects of niacin.However, recent data have indicated that niacin also decreases C-reactive protein levels, 6 improves endothelial dysfunction, 7,8 increases the endothelial and leukocyte oxidation-reduction (redox) state in vitro, 9 inhibits cytokine-induced monocyte adhesion to human endothelial cells, 9,10 improves plaque stability, and reduces thrombosis. 11 It...
Aims/hypothesis Hyperglycaemia, one of the main features of diabetes, results in non-enzymatic glycation of plasma proteins, including apolipoprotein A-I (apoA-I), the most abundant apolipoprotein in HDL. The aim of this study was to determine how glycation affects the structure of apoA-I and its ability to activate lecithin:cholesterol acyltransferase (LCAT), a key enzyme in reverse cholesterol transport. Materials and methods Discoidal reconstituted HDL (rHDL) containing phosphatidylcholine and apoA-I ([A-I] rHDL) were prepared by the cholate dialysis method and glycated by incubation with methylglyoxal. Glycation of apoA-I was quantified as the reduction in detectable arginine, lysine and tryptophan residues. Methylglyoxal-AGE adduct formation in apoA-I was assessed by immunoblotting. (A-I)rHDL size and surface charge were determined by non-denaturing gradient gel electrophoresis and agarose gel electrophoresis, respectively. The kinetics of the LCAT reaction was investigated by incubating varying concentrations of discoidal (A-I)rHDL with a constant amount of purified enzyme. The conformation of apoA-I was assessed by surface plasmon resonance. Results Methylglyoxal-mediated modifications of the arginine, lysine and tryptophan residues in lipid-free and lipidassociated apoA-I were time-and concentration-dependent. These modifications altered the conformation of apoA-I in regions critical for LCAT activation and lipid binding. They also decreased (A-I)rHDL size and surface charge. The rate of LCAT-mediated cholesterol esterification in (A-I)rHDL varied according to the level of apoA-I glycation and progressively decreased as the extent of apoA-I glycation increased. Conclusions/interpretation It is concluded that glycation of apoA-I may adversely affect reverse cholesterol transport in subjects with diabetes.
Spherical high density lipoprotein (sHDL), a key player in reverse cholesterol transport and the most abundant form of HDL, is associated with cardiovascular diseases. Small angle neutron scattering with contrast variation was used to determine the solution structure of protein and lipid components of reconstituted sHDL. Apolipoprotein A1, the major protein of sHDL, forms a hollow structure that cradles a central compact lipid core. Three apoA1 chains are arranged within the low resolution structure of the protein component as one of three possible global architectures: (i) a helical dimer with a hairpin (HdHp), (ii) three hairpins (3Hp), or (iii) an integrated trimer (iT) in which the three apoA1 monomers mutually associate over a portion of the sHDL surface. Cross-linking and mass spectrometry analyses help to discriminate among the three molecular models and are most consistent with the HdHp overall architecture of apoA1 within sHDL.Epidemiological studies firmly establish that circulating levels of high density lipoprotein (HDL) cholesterol and apolipoprotein A1 (apoA1), 2 the major protein constituent of HDL particles, are inversely associated with atherosclerotic heart disease risk (1-3). Moreover, genetic studies further confirm a strong mechanistic link between HDL and apoA1 and cardiovascular disease (4 -8). Defined by its buoyant density characteristics, HDL represent a heterogeneous group of particles with varied lipid composition and protein content that participate in diverse biological functions ranging from lipid transport to innate immune functions. For example, HDL serves as an acceptor of cholesterol from peripheral tissue macrophages and promotes lipid transport through delivery of cholesterol to the liver and steroidogenic tissues (9 -11). HDL also mediates systemic anti-inflammatory and anti-oxidant functions (12-14), and HDL-associated proteins can play critical host defense functions (15). ApoA1 represents nearly three-quarters of the protein content of HDL by mass, and it plays a central functional role in facilitating the numerous biological activities of HDL. Typically present at 2-4 molecules/particle depending upon the degree of HDL maturation, apoA1 serves as the fundamental structural element of the particle (16, 17) and is critical for specific interactions with proteins involved in HDL biogenesis (18, 19), maturation and remodeling (20,21), and recognition by target organ receptors (22,23).Because HDL can be generated in a relatively homogenous form, most structural studies of HDL have focused on reconstituted nascent HDL, a particle composed of two molecules of apoA1 associated with phospholipid and free cholesterol (16,17). Early small angle neutron scattering (SANS) and small angle x-ray scattering (SAXS) studies of nascent HDL particles were reported nearly 3 decades ago and are consistent with an outer protein layer relative to a central lipid core (24,25). Current structural models of nascent HDL have an anti-parallel apoA1 chain orientation and posit that the protein exists...
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