1,721,249 research outputs found
Raising HDL cholesterol for cardiovascular disease prevention : is this still feasible?
No full textPlasma high-density lipoprotein cholesterol (HDLC) has received considerable attention as a potential therapeutic target to further reduce cardiovascular risk in the statin era. However, doubts about the clinical benefit achievable with treatments enhancing plasma HDLC levels have been raised by the premature termination of a large phase 3 trial with torcetrapib-the most potent and furthest developed HDLC-raising compound-resulting from excess mortality in patients receiving the drug. The causes of torcetrapib failure are unknown and may be related to the drug's mode of action, off-target toxic effects, or a mixture of both. The failure of torcetrapib does not mean that the concept of targeting HDL in cardiovascular prevention is dead. Other HDLC-raising therapies, which act through disparate molecular mechanisms, are in various stages of preclinical and clinical development. The alternative is the direct administration of synthetic HDL, which has proven activity on atherosclerosis regression in coronary patients
High density lipoprotein and coronary heart disease: insights from mutations leading to low high density lipoprotein
No full textHypoalphalipoproteinemia can result from defects in the genes encoding apolipoprotein A-I, the major protein component of HDL, or enzymes that are critical for the formation/maturation of mature HDL. Recent information contradicts earlier findings, suggesting that most of the affected subjects are at increased risk of developing coronary heart disease, independent of the mutated gene. A possible exception is represented by mutations in the apolipoprotein A-I gene leading to structural variants, that might even exert a protective effect against atherosclerosis
High-density lipoprotein quantity or quality for cardiovascular prevention
No full textPlasma concentrations of HDL cholesterol (HDL-C) are strongly and inversely associated with cardiovascular risk, leading to the concept that therapies to enhance plasma HDL-C levels would be anti-atherogenic and protective against cardiovascular events. However, HDL are highly heterogeneous, with subclasses that can be separated and identified according to density, size, charge, and protein composition. There is evidence that these subclasses may differ in their functional anti-atherogenic properties. As a snapshot of the steady-state cholesterol carried by all HDL subclasses together, the individual HDL-C measurement is insufficient to capture the structural and functional variation in HDL particles. This review addresses the current knowledge on the structural and functional heterogeneity of HDL particles, and their relationship to cardiovascular disease, in the attempt of answering the question on whether certain subclasses of HDL may be better predictors of cardiovascular risk than HDL-C, and may be better targets than HDL-C for further improving cardiovascular disease reduction in the statin era
Endothelial protection by high-density lipoproteins: from bench to bedside
No full textThere are several potential mechanisms by which HDLs protect against the development of vascular disease. One relates to the unique ability of these lipoproteins to remove cholesterol from the arterial wall. Another is the ability of HDL to prevent and eventually correct endothelial dysfunction, a key variable in the pathogenesis of atherosclerosis and its complications. HDLs help maintain endothelial integrity, facilitate vascular relaxation, inhibit blood cell adhesion to vascular endothelium, reduce platelet aggregability and coagulation, and may favor fibrinolysis. These functions of HDLs complement their activity in arterial cholesterol removal by providing an excellent rationale for favorably influencing pathological processes underlying a variety of clinical conditions, such as accelerated atherosclerosis, acute coronary syndromes, and restenosis after coronary angioplasty, through a chronic or acute elevation of plasma HDL concentration
High-density lipoproteins: a therapeutic target for atherosclerotic cardiovascular disease
No full textDespite great progress being made during the last two decades in cardiovascular disease prevention, especially by lowering low-density lipoprotein-cholesterol with statins, cardiovascular events continue to occur. Plasma high-density lipoprotein (HDL) exerts multiple protective effects on the arterial wall, through promotion of reverse cholesterol transport, prevention of endothelial dysfunction and inhibition of lipid oxidation. Therapeutic interventions raising plasma HDL levels or directly mimicking its beneficial effects represent the next frontier in the prevention and treatment of cardiovascular disease
HDL and cholesterol handling in the brain
No full textCholesterol is an essential component of both the peripheral nervous system and central nervous system (CNS) of mammals. Brain cholesterol is synthesized in situ by astrocytes and oligodendrocytes and is almost completely isolated from other pools of cholesterol in the body, but a small fraction can be taken up from the circulation as 27-hydroxycholesterol, or via the scavenger receptor class B type I. Glial cells synthesize native high-density lipoprotein (HDL)-like particles, which are remodelled by enzymes and lipid transfer proteins, presumably as it occurs in plasma. The major apolipoprotein constituent of HDL in the CNS is apolipoprotein E, which is produced by astrocytes and microglia. Apolipoprotein A-I, the major protein component of plasma HDL, is not synthesized in the CNS, but can enter and become a component of CNS lipoproteins. Low HDL-C levels have been shown to be associated with cognitive impairment and various neurodegenerative diseases. On the contrary, no clear association with brain disorders has been shown in genetic HDL defects, with the exception of Tangier disease. Mutations in a wide variety of lipid handling genes can result in human diseases, often with a neuronal phenotype caused by dysfunctional intracellular lipid trafficking
Recombinant apolipoproteins for the treatment of vascular diseases
No full textThe protein components of human lipoproteins, apolipoproteins, allow the redistribution of cholesterol from the arterial wall to other tissues and exert beneficial effects on systems involved in the development of arterial lesions, like inflammation and hemostasis. Because of these properties, the antiatherogenic apolipoproteins, particularly apo A-I and apo E, may provide an innovative approach to the management of vascular diseases. The recent availability of extractive or biosynthetic molecules is allowing a detailed overview of their therapeutic potential in a number of animal models of arterial disease. Infusions of apo E, or more dramatically, of apo A-I, both recombinant or extractive, cause a direct reduction of the atherosclerotic burden in experimental animals. Naturally, as the apo A-I(Milano) (apo A- I(M)) dimer, or engineered recombinant apolipoproteins with prolonged permanence in plasma and improved function may offer an even better approach to the therapeutic handling of arterial disease. This progress will go on in parallel with innovations in the technologies for direct, non invasive assessments of human atherosclerosis, thus allowing closer monitoring of this potential new approach to therapy
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