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New Lipid Lowering Therapies for Cardiovascular and Metabolic Diseases: Lessons...
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New Lipid Lowering Therapies for Cardiovascular and Metabolic Diseases: Lessons from the Past and Future Challenges

A special issue of Diseases (ISSN 2079-9721). This special issue belongs to the section "Cardiology".

Deadline for manuscript submissions: closed (31 December 2018) | Viewed by 68827

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Dr. Ahmed Bakillah

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Guest Editor
King Abdullah International Medical Center (KAIMRC), Eastern Region, King Saud Bin Abdul-Aziz University of Health Sciences, Ministry of National Guards- Health Affairs, Mail Code 520, PO. Box 6664, AL Asha 31982, Saudi Arabia
Interests: cardiovascular diseases; diabetes; obesity; atherosclerosis, biomarkers; metabolic syndrome; dyslipidemia; lipid and lipoprotein metabolism; diabetic vascular complications
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Remarkable research efforts have been made in lowering plasma cholesterol levels by the widespread use of statins resulting in significant reduction of death rate by ~30%–40%. Despite all these efforts, cardiovascular disease (CVD) continue to be the leading cause of mortality worldwide. Current approaches for the prevention and treatment of CVD are not fully effective in terms of risk reduction due to “residual risk” even when using a number of statin-combined therapeutic strategies. Thus, it has become obvious that development and validation of new pharmacological intervention may contribute to a better assessment of CVD risk and help in implementing new therapeutic strategies for high risk patients. After recent failure with cholesteryl ester transfer protein inhibitors, effective lipid lowering drugs emerged as new revolutionizing lipid-lowering therapy. In this context, human anti-PCSK9 antibodies have been shown in a wide range of patients, including those with statins intolerance, to significantly decrease plasma cholesterol by ~50%–70% with no alarming safety signals.

This Special Issue will provide an open access opportunity to publish research work and review articles related to recent advances in the field of CVD, new molecular insights and potential therapeutic strategies for better patient diagnosis and disease prevention.

Dr. Ahmed Bakillah
Guest Editor

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Keywords

  • cardiovascular disease
  • lipids and lipoproteins
  • LDL cholesterol
  • statin
  • atherosclerosis
  • dyslipidemia
  • hypercholesterolemia
  • clinical trials
  • cardiovascular risk
  • cholesterol lowering drugs

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Published Papers (11 papers)

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Research

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12 pages, 8296 KiB  
Article
Genomic Influence in the Prevention of Cardiovascular Diseases with a Sterol-Based Treatment
by Ismael San Mauro Martín, Javier Andrés Blumenfeld Olivares, Eva Pérez Arruche, Esperanza Arce Delgado, María José Ciudad Cabañas, Elena Garicano Vilar and Luis Collado Yurrita
Diseases 2018, 6(2), 24; https://doi.org/10.3390/diseases6020024 - 3 Apr 2018
Cited by 4 | Viewed by 3897
Abstract
Raised serum cholesterol concentration is a well-established risk factor in cardiovascular disease. In addition, genetic load may have an indirect influence on cardiovascular risk. Plant-based sterol-supplemented foods are recommended to help reduce the serum low-density lipoprotein cholesterol level. The objective was to analyse [...] Read more.
Raised serum cholesterol concentration is a well-established risk factor in cardiovascular disease. In addition, genetic load may have an indirect influence on cardiovascular risk. Plant-based sterol-supplemented foods are recommended to help reduce the serum low-density lipoprotein cholesterol level. The objective was to analyse the influence of different polymorphisms in hypercholesterolemia patients following a dietary treatment with plant sterols. A randomised double-blind cross-over controlled clinical trial was carried out in 45 people (25 women). Commercial milk, containing 2.24 g of sterols, was ingested daily during a 3-week period, and then the same amount of skim milk, without sterols, was consumed daily during the 3-week placebo phase. Both phases were separated by a washout period of 2 weeks. At the beginning and end of each phase, blood draws were performed. Genes LIPC C-514T and APOA5 C56G are Ser19Trp carriers and greatly benefit from sterol intake in the diet. LIPC C-514T TT homozygous carriers had lower low-density lipoprotein cholesterol (LDL-c) levels than CC homozygote and CT heterozygote carriers after the ingestion of plant sterols (p = 0.001). These two genes also showed statistically significant changes in total cholesterol levels (p = 0.025; p = 0.005), and no significant changes in high-density lipoprotein (HDL) cholesterol levels (p = 0.032; p = 0.003), respectively. No statistically significant differences were observed for other genes. Further studies are needed to establish which genotype combinations would be the most protective against hypercholesterolemia. Full article
(This article belongs to the Special Issue New Lipid Lowering Therapies for Cardiovascular and Metabolic Diseases: Lessons from the Past and Future Challenges)
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10 pages, 903 KiB  
Article
Rosuvastatin Improves Vaspin Serum Levels in Obese Patients with Acute Coronary Syndrome
by Hayder M. Al-kuraishy, Ali I. Al-Gareeb and Ali K. Al-Buhadilly
Diseases 2018, 6(1), 9; https://doi.org/10.3390/diseases6010009 - 16 Jan 2018
Cited by 28 | Viewed by 4504
Abstract
Adipose tissue-derived serine protease inhibitor (vaspin), which has endocrine and local roles in atherosclerosis growth, is also synthesized by adipose tissue; it was found that vaspin was negatively correlated with blood pressure in obese patients, while vaspin levels were decreased in endothelial dysfunction. [...] Read more.
Adipose tissue-derived serine protease inhibitor (vaspin), which has endocrine and local roles in atherosclerosis growth, is also synthesized by adipose tissue; it was found that vaspin was negatively correlated with blood pressure in obese patients, while vaspin levels were decreased in endothelial dysfunction. The aim of the present study was to determine rosuvastatin modulation effects on serum vaspin levels in acute coronary syndrome (ACS) with class I obesity. A total number of seventy patients with acute coronary syndrome previously and currently treated with rosuvastatin was compared to 40 patients with IHD not treated by rosuvastatin as a control. Vaspin serum levels were higher in rosuvastatin-treated patients with acute coronary syndrome compared to the patients with acute coronary syndrome not treated by rosuvastatin, p < 0.01. Additionally, in the rosuvastatin-treated group, patients with STEMI showed higher vaspin serum levels compared to NSTEMI p < 0.01. Conclusion: Rosuvastatin significantly increases vaspin serum levels in acute coronary syndrome. Full article
(This article belongs to the Special Issue New Lipid Lowering Therapies for Cardiovascular and Metabolic Diseases: Lessons from the Past and Future Challenges)
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Review

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4 pages, 182 KiB  
Review
The Role of Statins in the Management of Patients Undergoing Coronary Artery Bypass Grafting
by Dimitrios Siskos and Konstantinos Tziomalos
Diseases 2018, 6(4), 102; https://doi.org/10.3390/diseases6040102 - 11 Nov 2018
Cited by 1 | Viewed by 3917
Abstract
Each year, a large number of patients undergo coronary artery bypass grafting surgery (CABG) worldwide. Accumulating evidence suggests that the preoperative administration of statins might be useful in preventing adverse events after CABG. In the present review, we discuss the role of statins [...] Read more.
Each year, a large number of patients undergo coronary artery bypass grafting surgery (CABG) worldwide. Accumulating evidence suggests that the preoperative administration of statins might be useful in preventing adverse events after CABG. In the present review, we discuss the role of statins in the perioperative management of patients undergoing CABG. Preoperative administration of statins in these patients substantially reduces the risk of postoperative atrial fibrillation and shortens hospital and intensive care unit (ICU) stay. Atorvastatin appears to be more effective, particularly when administered at high doses. Given these benefits and the safety of statins, their administration should be considered in patients undergoing CABG, even though the statins do not appear to affect the incidence of cardiovascular events and overall mortality perioperatively. Full article
(This article belongs to the Special Issue New Lipid Lowering Therapies for Cardiovascular and Metabolic Diseases: Lessons from the Past and Future Challenges)
10 pages, 736 KiB  
Review
Judicious Use of Lipid Lowering Agents in the Management of NAFLD
by Umair Iqbal, Brandon J. Perumpail, Nimy John, Sandy Sallam, Neha D. Shah, Waiyee Kwong, George Cholankeril, Donghee Kim and Aijaz Ahmed
Diseases 2018, 6(4), 87; https://doi.org/10.3390/diseases6040087 - 24 Sep 2018
Cited by 12 | Viewed by 6901
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the Western world. NAFLD encompasses a spectrum of histological features, including steatosis, steatohepatitis with balloon degeneration, and hepatic fibrosis leading to cirrhosis. In patients with advanced liver damage, [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the Western world. NAFLD encompasses a spectrum of histological features, including steatosis, steatohepatitis with balloon degeneration, and hepatic fibrosis leading to cirrhosis. In patients with advanced liver damage, NAFLD is associated with an increased risk of hepatocellular carcinoma. Diabetes mellitus, hypertension, and dyslipidemia are components of metabolic syndrome and are commonly associated with NAFLD. Cardiovascular disease is the leading cause of mortality in patients with NAFLD. Therefore, it is important to pre-emptively identify and proactively treat conditions like hyperlipidemia in an effort to favorably modify the risk factors associated with cardiovascular events in patients with NAFLD. The management of hyperlipidemia has been shown to reduce cardiovascular mortality and improve histological damage/biochemical abnormalities associated with non-alcoholic steatohepatitis (NASH), a subset of NAFLD with advance liver damage. There are no formal guidelines available regarding the use of anti-hyperlipidemic drugs, as prospective data are lacking. The focus of this article is to discuss the utility of lipid-lowering drugs in patients with NAFLD. Full article
(This article belongs to the Special Issue New Lipid Lowering Therapies for Cardiovascular and Metabolic Diseases: Lessons from the Past and Future Challenges)
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9 pages, 556 KiB  
Review
Regulation of Sphingolipid Metabolism by MicroRNAs: A Potential Approach to Alleviate Atherosclerosis
by Zainab Jahangir, Ahmed Bakillah and Jahangir Iqbal
Diseases 2018, 6(3), 82; https://doi.org/10.3390/diseases6030082 - 17 Sep 2018
Cited by 5 | Viewed by 4842
Abstract
The rapidly expanding field of bioactive lipids is exemplified by the many sphingolipids, which are structurally and functionally diverse molecules with significant physiologic functions. These sphingolipids are main constituents of cellular membranes and have been found associated with plasma lipoproteins, and their concentrations [...] Read more.
The rapidly expanding field of bioactive lipids is exemplified by the many sphingolipids, which are structurally and functionally diverse molecules with significant physiologic functions. These sphingolipids are main constituents of cellular membranes and have been found associated with plasma lipoproteins, and their concentrations are altered in several metabolic disorders such as atherosclerosis, obesity, and diabetes. Understanding the mechanisms that regulate their biosynthesis and secretion may provide novel information that might be amenable to therapeutic targeting in the treatment of these diseases. Several sphingolipid synthesis genes have been targeted as potential therapeutics for atherosclerosis. In recent years, significant progress has been made in studying the role of microRNAs (miRNAs) in lipid metabolism. However, little effort has been made to investigate their role in sphingolipid metabolism. Sphingolipid biosynthetic pathways involve various enzymes that lead to the formation of several key molecules implicated in atherosclerosis, and the identification of miRNAs that regulate these enzymes could help us to understand these complex pathways better and may prove beneficial in alleviating atherosclerosis. Full article
(This article belongs to the Special Issue New Lipid Lowering Therapies for Cardiovascular and Metabolic Diseases: Lessons from the Past and Future Challenges)
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6 pages, 566 KiB  
Review
Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia
by Constantine E. Kosmas, Alba Muñoz Estrella, Andreas Sourlas, Delia Silverio, Elizabeth Hilario, Peter D. Montan and Eliscer Guzman
Diseases 2018, 6(3), 63; https://doi.org/10.3390/diseases6030063 - 13 Jul 2018
Cited by 68 | Viewed by 13022
Abstract
The discovery of proprotein convertase subtilisin-kexin type 9 (PCSK9), a serine protease which binds to the low-density lipoprotein (LDL) receptors and targets the receptors for lysosomal degradation, offered an additional route through which plasma LDL-cholesterol (LDL-C) levels can be controlled. Initially, the therapeutic [...] Read more.
The discovery of proprotein convertase subtilisin-kexin type 9 (PCSK9), a serine protease which binds to the low-density lipoprotein (LDL) receptors and targets the receptors for lysosomal degradation, offered an additional route through which plasma LDL-cholesterol (LDL-C) levels can be controlled. Initially, the therapeutic approaches to reduce circulating levels of PCSK9 were focused on the use of monoclonal antibodies. To that effect, evolocumab and alirocumab, two human monoclonal antibodies directed against PCSK9, given on a background of statin therapy, have been shown to markedly decrease LDL-C levels and significantly reduce cardiovascular risk. The small interfering RNA (siRNA) molecules have been used recently to target the hepatic production of PCSK9. siRNA interferes with the expression of specific genes with complementary nucleotide sequences by affecting the degradation of mRNA post-transcription, thus preventing translation. Inclisiran is a long-acting, synthetic siRNA directed against PCSK9 and it has been shown to significantly decrease hepatic production of PCSK9 and cause a marked reduction in LDL-C levels. This review aims to present and discuss the current clinical and scientific evidence pertaining to inclisiran, which is a new promising agent in the management of hypercholesterolemia. Full article
(This article belongs to the Special Issue New Lipid Lowering Therapies for Cardiovascular and Metabolic Diseases: Lessons from the Past and Future Challenges)
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11 pages, 1094 KiB  
Review
CVD Risk Stratification in the PCSK9 Era: Is There a Role for LDL Subfractions?
by Christian Abendstein Kjellmo, Anders Hovland and Knut Tore Lappegård
Diseases 2018, 6(2), 45; https://doi.org/10.3390/diseases6020045 - 27 May 2018
Cited by 9 | Viewed by 6740
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce the risk of cardiovascular events and all-cause mortality in patients at high risk of cardiovascular disease (CVD). Due to high costs and unknown long-term adverse effects, critical evaluation of patients considered for PCSK9 inhibitors is [...] Read more.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce the risk of cardiovascular events and all-cause mortality in patients at high risk of cardiovascular disease (CVD). Due to high costs and unknown long-term adverse effects, critical evaluation of patients considered for PCSK9 inhibitors is important. It has been proposed that measuring low-density lipoprotein (LDL) subfractions, or LDL particle numbers (LDL-P), could be of value in CVD risk assessment and may identify patients at high risk of CVD. This review evaluates the evidence for the use of LDL subfractions, or LDL-P, when assessing CVD risk in patients for whom PCSK9 inhibitors are considered as a lipid-lowering therapy. Numerous methods for measuring LDL subfractions and LDL-P are available, but several factors limit their availability. A lack of standardization makes comparison between the different methods challenging. Longitudinal population-based studies have found an independent association between different LDL subfractions, LDL-P, and an increased risk of cardiovascular events, but definitive evidence that these measurements add predictive value to the standard risk markers is lacking. No studies have proven that these measurements improve clinical outcomes. PCSK9 inhibitors seem to be effective at lowering all LDL subfractions and LDL-P, but any evidence that measuring LDL subfractions and LDL-P yield clinically useful information is lacking. Such analyses are currently not recommended when considering whether to initiate PCKS9 inhibitors in patients at risk of CVD. Full article
(This article belongs to the Special Issue New Lipid Lowering Therapies for Cardiovascular and Metabolic Diseases: Lessons from the Past and Future Challenges)
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13 pages, 296 KiB  
Review
Management of Dyslipidemia in Type 2 Diabetes: Recent Advances in Nonstatin Treatment
by Kazutoshi Sugiyama and Yoshifumi Saisho
Diseases 2018, 6(2), 44; https://doi.org/10.3390/diseases6020044 - 24 May 2018
Cited by 3 | Viewed by 6594 | Correction
Abstract
Dyslipidemia is a major risk factor for cardiovascular disease (CVD), which is the leading cause of morbidity and mortality in type 2 diabetes (T2DM). Statins have played a crucial role in its management, but residual risk remains since many patients cannot achieve their [...] Read more.
Dyslipidemia is a major risk factor for cardiovascular disease (CVD), which is the leading cause of morbidity and mortality in type 2 diabetes (T2DM). Statins have played a crucial role in its management, but residual risk remains since many patients cannot achieve their desired low-density lipoprotein cholesterol (LDL-C) level and up to 20% of patients are statin-intolerant, experiencing adverse events perceived to be caused by statins, most commonly muscle symptoms. Recently, great advances have been made in nonstatin treatment with ezetimibe, a cholesterol absorption inhibitor, and proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs), all showing a proven benefit with an excellent safety profile in cardiovascular outcome trials. This review summarizes the key aspects and the evolving role of these agents in the management of dyslipidemia in patients with T2DM, along with a brief introduction of novel drugs currently in development. Full article
(This article belongs to the Special Issue New Lipid Lowering Therapies for Cardiovascular and Metabolic Diseases: Lessons from the Past and Future Challenges)
16 pages, 631 KiB  
Review
Lipid Target in Very High-Risk Cardiovascular Patients: Lesson from PCSK9 Monoclonal Antibodies
by Giovanni Ciccarelli, Saverio D’Elia, Michele De Paulis, Paolo Golino and Giovanni Cimmino
Diseases 2018, 6(1), 22; https://doi.org/10.3390/diseases6010022 - 17 Mar 2018
Cited by 11 | Viewed by 5093
Abstract
The role of low-density lipoproteins (LDLs) as a major risk factor for cardiovascular disease has been demonstrated by several epidemiological studies. The molecular basis for LDLs in atherosclerotic plaque formation and progression is not completely unraveled yet. Pharmacological modulation of plasma LDL-C concentrations [...] Read more.
The role of low-density lipoproteins (LDLs) as a major risk factor for cardiovascular disease has been demonstrated by several epidemiological studies. The molecular basis for LDLs in atherosclerotic plaque formation and progression is not completely unraveled yet. Pharmacological modulation of plasma LDL-C concentrations and randomized clinical trials addressing the impact of lipid-lowering interventions on cardiovascular outcome have clearly shown that reducing plasma LDL-C concentrations results in a significant decrease in major cardiovascular events. For many years, statins have represented the most powerful pharmacological agents available to lower plasma LDL-C concentrations. In clinical trials, it has been shown that the greater the reduction in plasma LDL-C concentrations, the lower the rate of major cardiovascular events, especially in high-risk patients, because of multiple risk factors and recurrent events. However, in a substantial number of patients, the recommended LDL target is difficult to achieve because of different factors: genetic background (familial hypercholesterolemia), side effects (statin intolerance), or high baseline plasma LDL-C concentrations. In the last decade, our understanding of the molecular mechanisms involved in LDL metabolism has progressed significantly and the key role of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged. This protein is an enzyme able to bind the LDL receptors (LDL-R) on hepatocytes, favoring their degradation. Blocking PCSK9 represents an intriguing new therapeutic approach to decrease plasma LDL-C concentrations, which in recent studies has been demonstrated to also result in a significant reduction in major cardiovascular events. Full article
(This article belongs to the Special Issue New Lipid Lowering Therapies for Cardiovascular and Metabolic Diseases: Lessons from the Past and Future Challenges)
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1234 KiB  
Review
Anacetrapib, a New CETP Inhibitor: The New Tool for the Management of Dyslipidemias?
by Theodosios D. Filippatos, Anastazia Kei and Moses S. Elisaf
Diseases 2017, 5(4), 21; https://doi.org/10.3390/diseases5040021 - 29 Sep 2017
Cited by 16 | Viewed by 7349
Abstract
Cholesteryl ester transfer protein (CETP) inhibitors significantly increase serum high-density lipoprotein cholesterol (HDL) cholesterol levels and decrease low-density lipoprotein cholesterol (LDL) cholesterol concentration. However, three drugs of this class failed to show a decrease of cardiovascular events in high-risk patients. A new CETP [...] Read more.
Cholesteryl ester transfer protein (CETP) inhibitors significantly increase serum high-density lipoprotein cholesterol (HDL) cholesterol levels and decrease low-density lipoprotein cholesterol (LDL) cholesterol concentration. However, three drugs of this class failed to show a decrease of cardiovascular events in high-risk patients. A new CETP inhibitor, anacetrapib, substantially increases HDL cholesterol and apolipoprotein (Apo) AI levels with a profound increase of large HDL2 particles, but also pre-β HDL particles, decreases LDL cholesterol levels mainly due to increased catabolism of LDL particles through LDL receptors, decreases lipoprotein a (Lp(a)) levels owing to a decreased Apo (a) production and, finally, decreases modestly triglyceride (TRG) levels due to increased lipolysis and increased receptor-mediated catabolism of TRG-rich particles. Interestingly, anacetrapib may be associated with a beneficial effect on carbohydrate homeostasis. Furthermore, the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification (REVEAL) trial showed that anacetrapib administration on top of statin treatment significantly reduces cardiovascular events in patients with atherosclerotic vascular disease without any significant increase of adverse events despite its long half-life. Thus, anacetrapib could be useful for the effective management of dyslipidemias in high-risk patients that do not attain their LDL cholesterol target or are statin intolerable, while its role in patients with increased Lp(a) levels remains to be established. Full article
(This article belongs to the Special Issue New Lipid Lowering Therapies for Cardiovascular and Metabolic Diseases: Lessons from the Past and Future Challenges)
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Other

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5 pages, 550 KiB  
Perspective
Epigenetic Regulation of ATP-Binding Cassette Protein A1 (ABCA1) Gene Expression: A New Era to Alleviate Atherosclerotic Cardiovascular Disease
by Mohamed Zaiou and Ahmed Bakillah
Diseases 2018, 6(2), 34; https://doi.org/10.3390/diseases6020034 - 3 May 2018
Cited by 12 | Viewed by 5180
Abstract
The most important function of high density lipoprotein (HDL) is its ability to remove cholesterol from cells and tissues involved in the early stages of atherosclerosis back to the liver for excretion. The ATP-binding cassette transporters ABCA1 and ABCG1 are responsible for the [...] Read more.
The most important function of high density lipoprotein (HDL) is its ability to remove cholesterol from cells and tissues involved in the early stages of atherosclerosis back to the liver for excretion. The ATP-binding cassette transporters ABCA1 and ABCG1 are responsible for the major part of cholesterol efflux to HDL in macrophage foam cells. Thus, promoting the process of reverse cholesterol transport (RCT) by upregulating mainly ABCA1 remains one of the potential targets for the development of new therapeutic agents against atherosclerosis. Growing evidence suggests that posttranscriptional regulation of HDL biogenesis as well as modulation of ABCA1 expression are under the control of several genetic and epigenetic factors such as transcription factor (TFs), microRNAs (miRNAs) and RNA-binding proteins (RBPs).These factors may act either individually or in combination to orchestrate ABCA1 expression. Complementary to our recent work, we propose an exploratory model for the potential molecular mechanism(s) underlying epigenetic signature of ABCA1 gene regulation. Such a model may hopefully provide the basic framework for understanding the epigenetic regulation of RCT and contribute to the development of novel therapeutic strategies to alleviate the burden of cardiovascular diseases (CVD). Full article
(This article belongs to the Special Issue New Lipid Lowering Therapies for Cardiovascular and Metabolic Diseases: Lessons from the Past and Future Challenges)
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