1,721,192 research outputs found
New targets and developments in lipoproteins control
Full text linkGiuseppe Danilo Norata1–31Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Italy; 2Center for the Study of Atherosclerosis, Società Italiana Studio Aterosclerosi, Ospedale Bassini, Cinisello Balsamo, Italy; 3The Blizard Institute, Centre for Diabetes, Barts and The London School of Medicine and Dentistry, Queen Mary University, London, UKAbstract: Statins provide a very effective approach in reducing plasma cholesterol levels and cardiovascular risk. However, the proportion of patients who fail to achieve desirable plasma lipid levels ranges from 16%–53%, worldwide. This percentage reaches up to 80% in patients with familial hypercholesterolemia. Additionally, many patients are unable to tolerate statins, particularly at the highest approved dose level. New treatments that aggressively reduce lipid levels in patients with severe hypercholesterolemia, or those unable to reach their lipid targets, are therefore required. The most promising approaches in this context, such as inhibitors of the synthesis of apolipoprotein B (apoB) containing lipoproteins (apoB silencing or microsomal triglyceride transfer protein [MTP] inhibition) or proprotein convertase subtilisin/kexin type 9 (PCSK9) blockers, all decrease low-density lipoprotein (LDL) extensively. Increasing low levels of high-density lipoprotein (HDL) cholesterol via cholesteryl ester transfer protein inhibitors or apolipoprotein A-1 (ApoA-1) inducers and improving their quality with HDL or ApoA-1 mimetics represent also important options. Drugs affecting HDL, however, may not be all alike and require adequate scrutiny of the mechanisms involved. Until we have a better understanding of these issues, further LDL lowering in high-risk patients represents the soundest approach.Keywords: apolipoproteins, lipids, lipoprotein classes, hypercholesterolemia, synthesis, LDL lowerin
Inibitori di PCSK9 e dislipidemie: le evidenze cliniche
No full textElevated plasma LDL cholesterol (LDL-C) levels are associated with cardiovascular diseases and statin therapy was proven to decrease LDL-C and reduce cardiovascular death. However, in patients at high cardiovascular risk, achievement of optimal LDL-C levels is challenging, and therefore additional strategies for further loweing LDL-C levels are under development. Recently, silencing of apolipoprotein B gene and MTP inhibition have been approved for the treatment of patients with familial hypercholesterolemia, and there is great interest in the inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9). PCSK9 promotes the degradation of the LDL receptor. The inhibition of PCSK9 favors LDL catabolism and reduces plasma LDLC levels. Monoclonal antibodies against PCSK9 represent so far the most advanced approach in clinical development, with alirocumab, evolocumab and bococizumab under advanced clinical development. Recent data from the first phase III studies show LDL-C reduction in monotherapy and on top of statins. Long-term studies on cardiovascular endpoints are ongoing and the results will be crucial to translate the benefit of this promising approach into clinical practice
Triglyceride-rich lipoproteins from normotrygliceridemic subjects and hyperlipidemic patients differently affect endothelial cell activation and gene expression patterns
No full textLipid lowering activity of drugs affecting cholesterol absorption
No full textAIM: Dietary cholesterol absorption, endogenous cholesterol synthesis and biliary cholesterol excretion regulate whole body cholesterol balance as a result of biotransformation into bile acids or direct cholesterol excretion. Recent studies have significantly advanced our understanding of intestinal sterol absorption at molecular level. This review concentrates on two major issues: the mechanisms of sterol absorption, and the currently available or experimental drugs that affect this pathway. DATA SYNTHESIS: Nuclear hormone receptors, such as the liver X, farnesoid X and retinoid X receptors, regulate the absorption of dietary sterols by modulating the transcription of several genes involved in cholesterol metabolism, The ABC proteins transport dietary cholesterol from enterocytes back to the intestinal lumen, thus limiting the amount of absorbed cholesterol. By means of the same mechanism, ABC transporters also provide an efficient barrier against the absorption of plant sterols. Phytosterols, bile acid sequestrants, ezetimibe and ACAT inhibitors are possible means of affecting these pathways. CONCLUSION: In addition to providing an insight into the molecular mechanisms of sterol absorption, these recent findings may lead to new therapeutic options for the treatment of hypercholesterolemia. This is particularly true in the case of patients at high risk of coronary artery disease requiring aggressive lipid-lowering therapy combining a statin with drugs affecting cholesterol absorption in order to ensure the optimal management of dyslipidemia
Lecithin:cholesterol acyltransferase and vascular disease
No full textEvaluation of: Calabresi L, Baldassarre D, Castelnuovo S et al.: Functional lecithin:cholesterol acyltransferase is not required for efficient atheroprotection in humans. Circulation 120, 628-635 (2009). Lecithin:cholesterol acyltransferase (LCAT) is an HDL-associated enzyme responsible for esterifying free cholesterol to cholesteryl ester within the plasma compartment. Mutations in the LCAT gene can cause LCAT deficiency, a very rare metabolic disorder associated with two hypoalphalipoproteinemia syndromes; familial LCAT deficiency, characterized by complete lack of enzyme activity, and fish-eye disease, with a partially defective enzyme. As LCAT deficiency causes hypoalphalipoproteinemia, carriers should be at increased risk of coronary artery disease because of defective reverse cholesterol transport; however, owing to the relatively small number of cases available, this hypothesis has not been confirmed. Calabresi et al. take advantage of the availability of 13 LCAT-deficient families to investigate the extent of carotid preclinical atherosclerosis in these patients
Established and Emerging Approaches for the Management of Dyslipidaemia
Full text linkThe key role of dyslipidaemia in determining cardiovascular disease (CVD) has been proved beyond reasonable doubt, and therefore several dietary and pharmacological approaches have been developed. The discovery of statins has provided a very effective approach in reducing cardiovascular risk as documented by the results obtained in clinical trials and in clinical practice. The current efficacy of statins or other drugs, however, comes short of providing the benefit that could derive from a further reduction of LDL cholesterol (LDL-C) in high-risk and very high risk patients. Furthermore, experimental data clearly suggest that other lipoprotein classes beyond LDL play important roles in determining cardiovascular risk. For these reasons a number of new potential drugs are under development in this area. Aim of this review is to discuss the available and the future pharmacological strategies for the management of dyslipidemia
Triglyceride-rich lipoproteins and endothelial dysfunction : molecular mechanisms and gene expression studies
No full textMolecular mechanisms responsible for the anti-inflammatory and protective effect of high-density lipoprotein on the endothelium
No full textIn addition to their role in reverse cholesterol transport, high-density lipoproteins (HDLs) exert several beneficial effects, including the prevention and correction of endothelial dysfunction. HDLs promote endothelium proliferation and diminish endothelial apoptosis; they play a key role in vasorelaxation by increasing the release of nitric oxide and prostacyclin through the induction of the expression and the activity of endothelial nitric oxide synthase and the coupling of cyclo-oxygenase 2 and prostacyclin synthase. In addition, HDLs affect coagulation, fibrinolysis, platelet adhesion, adhesion molecules and protease expression, and exert antioxidant activity. These effects are achieved at the gene expression level and are dependent on the activation of several intracellular signalling pathways, including PI3K/Akt, extracellular signal-regulated kinase (ERK) 1/2, protein kinase C, and p38MAPK (mitogen-activated protein kinase). The complexity of the signalling pathways modulated by HDL reflects the different effects of the components of this class of lipoproteins such as apolipoproteins or lipids on endothelial cell gene expression and the subsequent observed modulation of endothelial function. The in vivo relevance of these findings to endothelial recovery during physiological or pathological conditions remain to be addressed; nevertheless, the results of clinical studies with synthetic HDL, apolipoprotein A-I mimetics and drugs selectively affecting HDL plasma levels and biological functions that are becoming available support the importance of the correction of endothelial function by HD
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