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Apolipoprotein Mimetic Peptides: Potential New Therapies for Cardiovascular Diseases.
Wolska, A, Reimund, M, Sviridov, DO, Amar, MJ, Remaley, AT
Cells. 2021;(3)
Abstract
Since the seminal breakthrough of treating diabetic patients with insulin in the 1920s, there has been great interest in developing other proteins and their peptide mimetics as therapies for a wide variety of other medical disorders. Currently, there are at least 60 different peptides that have been approved for human use and over 150 peptides that are in various stages of clinical development. Peptides mimetic of the major proteins on lipoproteins, namely apolipoproteins, have also been developed first as tools for understanding apolipoprotein structure and more recently as potential therapeutics. In this review, we discuss the biochemistry, peptide mimetics design and clinical trials for peptides based on apoA-I, apoE and apoC-II. We primarily focus on applications of peptide mimetics related to cardiovascular diseases. We conclude with a discussion on the limitations of peptides as therapeutic agents and the challenges that need to be overcome before apolipoprotein mimetic peptides can be developed into new drugs.
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RVX 208: A novel BET protein inhibitor, role as an inducer of apo A-I/HDL and beyond.
Ghosh, GC, Bhadra, R, Ghosh, RK, Banerjee, K, Gupta, A
Cardiovascular therapeutics. 2017;(4)
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Abstract
Low-density cholesterol (LDL) has been the prime target of currently available lipid-lowering therapies although current research is expanding the focus beyond LDL lowering and has included high-density cholesterol (HDL) also as the target. Bromo and extra-terminal (BET) proteins are implicated in the regulation of transcription of several regulatory genes and regulation of proinflammatory pathways. As atherosclerosis is an inflammatory pathway and studies showed that BET inhibition has a role in inhibiting inflammation, the concept of BET inhibition came in the field of atherosclerosis. RVX 208 is a novel, orally active, BET protein inhibitor and the only BET inhibitor currently available in the field of atherosclerosis. RVX 208 acts primarily by increasing apo A-I (apolipoprotein A-I) and HDL levels. RVX 208 has a novel action of increasing larger, more cardio-protective HDL particles. Post hoc analysis of Phase II trials also showed that RVX 208 reduced major adverse cardiovascular events (MACE) in treated patients, over and above that of apo A-I/HDL increasing action. This MACE reducing actions of RVX 208 were largely due to its novel anti-inflammatory actions. Currently, a phase III trial, BETonMACE, is recruiting patients to look for the effects of RVX 208 in patients with increased risk of atherosclerotic cardiovascular disease. So BET inhibitors act in multiple ways to inhibit and modulate atherosclerosis and would be an emerging and potential option in the management of multifactorial disease like coronary artery disease by inhibiting a single substrate. But we need long-term phase III trial data's to look for effects on real-world patients.
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Focus on lipids: high-density lipoprotein cholesterol and its associated lipoproteins in cardiac and renal disease.
Shin, HJ, McCullough, PA
Nephron. Clinical practice. 2014;(1-4):158-64
Abstract
High-density lipoprotein cholesterol (HDL-C) contains dozens of apoproteins that participate in normal cholesterol metabolism with a reliance on renal catabolism for clearance from the body. The plasma pool of HDL-C has been an excellent inverse predictor of cardiovascular events. However, when HDL-C concentrations have been manipulated with the use of niacin, fibric acid derivatives, and cholesteryl ester transferase protein inhibitors, there has been no improvement in outcomes in patients where the low-density lipoprotein cholesterol has been well treated with statins. Apolipoprotein L1 (APOL1) is one of the minor apoproteins of HDL-C, newly discovered in 1997. Circulating APOL1 is a 43-kDa protein mainly found in the HDL3 subfraction. In patients with chronic kidney disease (CKD), mutant forms of APOL1 have been associated with rapidly progressive CKD and end-stage renal disease (ESRD). Because mutant forms of APOL1 are more prevalent in African Americans compared to Caucasians, it may explain some of the racial disparities seen in the pool of patients with ESRD in the United States. Thus, HDL-C is an important lipoprotein carrying apoproteins that play roles in vascular and kidney disease.
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Apolipoprotein measurements: is more widespread use clinically indicated?
Davidson, MH
Clinical cardiology. 2009;(9):482-6
Abstract
Apolipoprotein (apo) B may be a more sensitive measure of atherogenicity than low-density lipoprotein cholesterol (LDL-C) and a better index for assessing cardiovascular risk. The refined risk assessment provided by apo B may be important in patients at high cardiometabolic risk such as those with diabetes mellitus or metabolic syndrome, as these conditions are often associated with normal LDL-C values but increased numbers of small, dense low-density lipoprotein (LDL) particles (indicating increased levels of apo B). Although apo B is not currently a treatment target in the United States cholesterol-lowering guidelines, a consensus conference endorsed by the American Diabetes Association and the American College of Cardiology recently recommended that apo B be added as a therapeutic target in patients at high cardiometabolic risk and in patients with clinical cardiovascular disease or diabetes. Suggested target goals are < 90 for high risk and < 80 mg/dL for highest risk patients. Current clinical data indicate that intensive statin therapy can lower apo B to meet this aggressive goal. While the proatherogenic/antiatherogenic ratio of apo B/apo A-I is a better risk discriminator than the single proatherogenic measurement (apo B), clinical trial data are lacking regarding the impact of increasing apo A-I and high-density lipoprotein on outcomes.
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Potential restoration of HDL function with apolipoprotein A-I mimetic peptide in end-stage renal disease.
Kaysen, GA
Kidney international. 2009;(4):359-61
Abstract
High-density lipoprotein (HDL) cholesterol level is low in dialysis patients. The HDL that is present is dysfunctional, failing to protect low-density lipoprotein (LDL) from oxidation and reduce levels of oxidized LDL. Addition of the orally absorbable amphipathic peptide 4-F to LDL obtained from dialysis patients protects LDL from oxidation in vitro and reduces the capacity of oxidized LDL to induce expression of monocyte chemoattractant protein-1 (MCP-1) by vascular endothelial function in culture, potentially providing a tool to reduce cardiovascular risk in dialysis patients.
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Effects of statins on high-density lipoproteins: a potential contribution to cardiovascular benefit.
McTaggart, F, Jones, P
Cardiovascular drugs and therapy. 2008;(4):321-38
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Abstract
PURPOSE The objective was to systematically review clinical trial data on the effects of statins on high-density lipoproteins (HDL) and to examine the possibility that this provides cardiovascular benefits in addition to those derived from reductions in low-density lipoproteins (LDL). METHODS The PubMed database was searched for publications describing clinical trials of atorvastatin, pravastatin, rosuvastatin, and simvastatin. On the basis of predefined criteria, 103 were selected for review. RESULTS Compared with placebo, statins raise HDL, measured as HDL-cholesterol (HDL-C) and apolipoprotein A-I (apo A-I); these elevations are maintained in the long-term. In hypercholesterolemia, HDL-C is raised by approximately 4% to 10%. The percentage changes are greater in patients with low baseline levels, including those with the common combination of high triglycerides (TG) and low HDL-C. These effects do not appear to be dose-related although there is evidence that, with the exception of atorvastatin, the changes in HDL-C are proportional to reductions in apo B-containing lipoproteins. The most likely explanation is a reduced rate of cholesteryl ester transfer protein (CETP)-mediated flow of cholesterol from HDL. There is some evidence that the statin effects on HDL reduce progression of atherosclerosis and risk of cardiovascular disease independently of reductions in LDL. CONCLUSION Statins cause modest increases in HDL-C and apo A-I probably mediated by reductions in CETP activity. It is plausible that such changes independently contribute to the cardiovascular benefits of the statin class but more studies are needed to further explore this possibility.
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HDL: bridging past and present with a look at the future.
Scanu, AM, Edelstein, C
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2008;(12):4044-54
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Abstract
Clinical and epidemiological studies have shown that HDLs, a class of plasma lipoproteins, heterogeneous in size and density, have an atheroprotective role attributed, for years, to their capacity to promote the efflux of cholesterol from activated cholesterol-loaded arterial macrophages. Recent studies, however, have recognized that the physical heterogeneity of HDLs is associated with multiple functions that involve both the protein and the lipid components of these particles. ApoA-I, quantitatively the major protein constituent, has an amphipathic structure suited for transport of lipids. It readily interacts with the ATP-binding cassette transporter ABCA1, the SR-B1 scavenger receptor; activates the enzyme lecithin-cholesterol acyl transferase (LCAT), which is critical for HDL maturation. It also has antioxidant and antiinflammatory properties, along with the HDL-associated enzymes paraoxonase, platelet activating factor acetylhydrolase (PAF), and glutathione peroxidase. Regarding the lipid moiety, an atheroprotective role has been recognized for lysosphingolipids, particularly sphingosine-1-phosphate (S1P). All of these atheroprotective functions are lost in the post-translational dependent dysfunctional plasma HDLs of subjects with systemic inflammation, coronary heart disease, diabetes, and chronic renal disease. The emerging notion that particle quality has more predictive power than quantity has stimulated further exploration of the HDL proteome, already revealing unsuspected pro- or antiatherogenic proteins/peptides associated with HDL.
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[Apolipoprotein B and A-I: cardiovascular risk factor?].
Forti, N, Diament, J
Revista da Associacao Medica Brasileira (1992). 2007;(3):276-82
Abstract
Apolipoprotein (apo) B is present in atherogenic lipoproteins (remnant Qm and VLDL, LDL and Lp (a)) and apo A is present in non-atherogenic lipoprotein (HDL). Measurement of the apos is automated, standardized, with a small variation of coefficient and does not require fasting blood samples. The authors reviewed clinical, epidemiological and therapeutic trials on hyperlipidemia with apo B and A-I evaluation. These works showed the importance of apo B and A-I as cardiovascular risk factors. Experts recommended apo B / apo A-I ratio as an alternative to TC / HDL-c ratio for risk estimate. Future positioning from the Guidelines is expected to include apos in individual risk prediction and as a therapeutic target. The authors suggest that, in clinical practice, measurement of apo B is necessary for coronary heart disease patients with desirable LDLc levels or when this assessment is not possible and the measurement of apo A-I if HDL-c values are very low.
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Apolipoproteins AI and B as therapeutic targets.
Charlton-Menys, V, Durrington, P
Journal of internal medicine. 2006;(5):462-72
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Abstract
Currently the apolipoprotein B:AI ratio integrates information about the potential for cardiovascular disease (CVD) risk reduction better than any other lipid or lipoprotein index. Certainly it could, with benefit, replace serum cholesterol and HDL cholesterol in the estimation of CVD risk. Defining the therapeutic target of statin therapy in terms of serum apolipoprotein B (apo B) rather than LDL cholesterol could also help to optimize statin treatment. Deciding whether a therapeutic response is adequate also requires knowledge of whether there is persisting hypertriglyceridaemia, because this gives an indication of whether small dense LDL is likely to have been satisfactorily reduced. Raising low levels of HDL, probably best measured as apo AI, may also prove to be an important aim of treatment. This is, however, a more complex issue and also depends on the mechanism by which a particular therapy alters HDL levels and on whether the capacity of HDL to perform its anti-inflammatory and antioxidative functions is restored. A meta-analysis of randomized clinical trials of statins in which apo B and apo AI have been reported could provide valuable information.
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Measurement and meaning of apolipoprotein AI and apolipoprotein B plasma levels.
Marcovina, S, Packard, CJ
Journal of internal medicine. 2006;(5):437-46
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Apolipoproteins AI and B are structural components of lipoprotein particles, and also determinants of the metabolic fate of the encapsulated lipid, cholesterol and triglyceride. Development of accurate assays for these apolipoproteins has opened the way for their use as predictors of coronary heart disease risk. Interpretation of AI and apo B levels is best undertaken with background knowledge of the metabolic status of an individual, especially the lipolytic capacity as reflected in the triglyceride concentration. Those with raised triglyceride, in general, not only have an elevated apo B/apo AI ratio, but also apo B-containing lipoproteins with a prolonged residence time and hence ample opportunity for modification and damage. Assessment of apolipoprotein levels is an aid to risk prediction and can be useful in tailoring treatment.