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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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2.
The Rise and Fall "ing" of the HDL Hypothesis.
Feghaly, JJ, Mooradian, AD
Drugs. 2020;(4):353-362
Abstract
Earlier epidemiological studies have shown an inverse correlation between high-density lipoprotein cholesterol (HDLc) and coronary heart disease (CHD). This observation along with the finding that reverse cholesterol transport is mediated by HDL, supported the hypothesis that the HDL molecule has a cardioprotective role. More recently, epidemiological data suggest a U-shaped curve correlating HDLc and CHD. In addition, randomized clinical trials of drugs that significantly increase plasma HDLc levels, such as nicotinic acid and cholesterol ester transfer protein (CETP) inhibitors failed to show a reduction in major adverse cardiovascular events. These observations challenge the hypothesis that HDL has a cardioprotective role. It is possible that HDL quality and function is optimal only when de novo synthesis of apo A-I occurs. Inhibition of turnover of HDL with currently available agents yields HDL molecules that are ineffective in reverse cholesterol transport. To test this hypothesis, newer therapeutic drugs that increase de novo production of HDL and apo A-I should be tested in clinical trials.
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3.
The HDL cholesterol/apolipoprotein A-I ratio: an indicator of cardiovascular disease.
Rhee, EJ, Byrne, CD, Sung, KC
Current opinion in endocrinology, diabetes, and obesity. 2017;(2):148-153
Abstract
PURPOSE OF REVIEW In multiple studies, the HDL cholesterol (HDL-C) concentration has been shown to be inversely associated with cardiovascular disease (CVD) and CVD risk. Based on this observation, increasing the plasma HDL-C concentration is thought to be a desirable strategy, in the 21st century, for decreasing the burden of CVD. RECENT FINDINGS Recent studies have shown that powerful HDL-C concentration-increasing drugs are ineffective for decreasing CVD. Increasing evidence now shows that HDL is an unstable and heterogeneous particle, and that 'HDL particle functionality' is far more important in atheroprotection than is the HDL-C level, alone. Apolipoprotein A-I (apoA-I) is the major protein component of HDL, and increasing evidence suggests that the ratio of HDL-C to apoA-I may give additional insight as a risk marker not just for CVD but also for all-cause and cancer mortality. SUMMARY In this review, we discuss the importance of HDL composition, apoA-I levels, and the HDL-C/apoA-I ratio for predicting CVD and mortality outcomes.
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4.
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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5.
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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6.
Apolipoprotein B and apolipopotein A-I in vascular risk prediction - a review.
Schmidt, C, Bergstrom, G
Current pharmaceutical design. 2014;(40):6289-98
Abstract
The concentration of low-density lipoprotein cholesterol has long been generally accepted as one of the strongest, independent risk factors for the development of cardiovascular disease. However, an increasing number of studies suggest that the ratio of apolipoprotein B (apoB) to apolipoprotein A-I (apoA-I) is a better risk predictor. In the present review, we focus on apoB and apoA-I as factors in predicting vascular risk in epidemiological studies only, and not in studies involving pharmaceutical intervention. The majority of studies in the present review show that apoB and the apoB/apoA-I ratio are independently and more strongly associated with vascular risk across varying age-groups and geographic regions than are conventional lipids, lipoproteins and lipid ratios.
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7.
The structure/function of apoprotein A-I mimetic peptides: an update.
Getz, GS, Reardon, CA
Current opinion in endocrinology, diabetes, and obesity. 2014;(2):129-33
Abstract
PURPOSE OF REVIEW To review recent advances in our understanding of the mechanism of action of apoprotein A-I (apoA-I) mimetic peptides and improved methods for the oral delivery of peptides. RECENT FINDINGS The apoA-I mimetic peptides are based on the structure of the major apoprotein of HDL with the expectation that they may also mimic some of the antiatherogenic functions of HDL. Recent work has provided insight into mechanisms by which they may be antioxidative and anti-inflammatory. In addition, recent work has shifted the focus of the site of action of the mimetic peptides to the small intestine from the plasma and HDL and suggests modulation of bioactive oxidized lipids in the intestine by the peptides may be a major antiatherogenic pathway. The development of transgenic tomatoes expressing an apoA-I mimetic peptide is a significant advance in the oral delivery of peptides as therapies for cardiovascular disease and other chronic inflammatory disorders. SUMMARY In the past year, there have been important advances in the field of apoA-I mimetic peptides, including the oral delivery of bioactive peptides. Further work is required to fully understand the molecular basis for the effect of the peptide on the intestine and bioactive oxidized lipids.
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8.
Newer therapeutic strategies to alter high-density lipoprotein level and function.
Bosch, N, Frishman, WH
Cardiology in review. 2014;(1):17-24
Abstract
Measurements of low levels of high-density lipoprotein (HDL) cholesterol have been identified as a risk factor for premature coronary artery disease, however, to date, current pharmacologic approaches for raising HDL have provided little benefit, if at all, in reducing cardiovascular outcomes. It has been shown that HDL can modify many aspects of plaque pathogenesis. Its most established role is in reverse cholesterol transportation, but HDL can also affect oxidation, inflammation, cellular adhesion, and vasodilatation. Considering these potential benefits of HDL, newer treatments have been developed to modify HDL activity, which include the use of oral cholesteryl ester transfer protein inhibitors, apolipoprotein (apo)A-I infusions, apoA-I mimetics, drugs to increase apoA-I synthesis, and agonists of the liver X receptor. These new therapies are reviewed in this article.
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Biomarkers associated with high-density lipoproteins in atherosclerotic kidney disease.
Rye, KA
Clinical and experimental nephrology. 2014;(2):247-50
Abstract
High-density lipoproteins (HDL) originate as discoidal particles that are rapidly converted by lecithin:cholesterol acyltransferase (LCAT) into the spherical particles that predominate in normal human plasma. Spherical HDL consist of multiple populations of particles that vary widely in size, composition and function. Human population studies have established that high plasma HDL cholesterol levels are associated with a reduced incidence of cardiovascular disease. The mechanistic basis of this relationship is not well understood, but most likely involves a number of the cardioprotective functions of HDL. These include the ability of apolipoprotein (apo) A-I, the main apolipoprotein constituent of HDL, to remove cholesterol from macrophages in the artery wall. HDL also have antioxidant and anti-inflammatory properties that are potentially cardioprotective. Evidence that some of these beneficial properties are compromised in people with diabetes and renal disease is emerging. Persistently elevated plasma glucose levels in people with diabetes and poor glycemic control can lead to irreversible, non-enzymatic glycation of plasma proteins, including apoA-I. Non-enzymatically glycated proteins are also prevalent in people with diabetes and end-stage renal disease who are at high cardiovascular risk. Evidence that non-enzymatically glycated apoA-I inhibits the LCAT reaction and impairs some of the cardioprotective properties of HDL is also emerging. This review is concerned with how non-enzymatic glycation of apoA-I affects the ability of LCAT to convert discoidal HDL into spherical HDL, how it affects cholesterol efflux from macrophages and how it affects the anti-inflammatory and antioxidant properties of HDL.
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10.
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.