Current Medicinal Chemistry - Volume 21, Issue 25, 2014

In the last few years there has been a large discussion on the properties of high density lipoprotein cholesterol (HDL-C). The main part of this debate concerns the role of HDL-C in predicting cardiovascular (CV) events and mortality, and in consequence, in reducing the residual risk [1]. It is connected to the fact that all large randomized controlled trials (RCTs) which were dedicated to investigate this role of HDL-C gave negative results [2]. HDL particles can be divided into different subpopulations/subfractions, according to their size, density, electrophoretic mobility, and apolipoprotein (Apo) composition. They are composed of the highest proportion of apolipoprotein A-I (apoA-I; 60% of the protein content), apoA-II (20% of the protein content), with small amounts of apoC, E, A-IV, D and J [3]. Their properties are also associated with the fact that HDL particles carry important anti-oxidant enzymes: paraoxonase-1 (PON1), platelet-activating factor acetyl hydrolase (PAF-AH), glutathione selenoperoxidase (GSPx), lecithin-cholesterol acyltransferase (LCAT) and phospholipid transfer protein (PLTP) [4-6]. The qualitative and quantitative content of lipids and Apos, as well as enzymes vary resulting in different HDL subclasses, which can be distinguished using different methods [4-7]. As for example, activities of HDL-associated enzymes such as LCAT, PON1and PAF-AH are much elevated in small, dense HDL-3c and these particles also have a predominance of apoJ, apoL-1 and apoF proteins and PLTP as well; in contrast, apoE, apoC-I, - II and -III occur predominantly in large, less dense HDL-2 particles [7-10]. Continuous intravascular remodeling of HDL particles during reverse cholesterol transport (RCT) also contributes to their heterogeneity – the nascent discoidal HDL particles are progressively lapidated to form, in succession, small, dense HDL-3 and then large HDL-2 particles by LCAT [8-10]. Despite our intensive knowledge on the structure of HDL particles, as well as HDL subfractions/subpopulations, we have still had very limitted, and often exclusive data on their properties and role in CV risk prediction [11]. As for instance, in some available studies it was shown that small HDL subfractions might significantly increase the risk of CVD (similarly to small dense low density lipoprotein cholesterol [LDL-C]). In others they were observed as being highly protective [11]. There are at least few explanations for that. The most important one is connected to the fact that there are many different methods of HDL subfractions/subpopulations analysis, which have been used in available studies. On the other hand, the CV risk of investigated patients in these studies was very different from primary prevention patients with concomitant CV risk factors, through subjects after acute coronary event/stroke, finishing with individuals with CVD and chronic kidney disease [11,12]. In all these subjects the role of HDL particles might be completely different, because their properties on a large degree depend on inflammation (as well as oxidative stress) intensity [1, 13]. The bigger the intensity of inflammation, the more the HDL particles with impaired functionality. Therefore, it might be that the size of HDL particles is not so important, and, according to our hypothesis, the more important question might be when, and at what stage of HDL metabolism these particles are the most prone to functional changes [1,7,13]. It needs to be also emphasized that most of the epidemiological studies and RCTs evaluated only the quantity of circulating HDL-C, but not the quality and functionality of its subclasses, and nowadays it seems to be commonly accepted that the functionality of HDL subclasses defines the anti-atherogenic quality of HDL [1,7,13,14]. In this respect, the new concept of "dysfunctional HDL", "pro-inflammatory HDL" or "pro-atherogenic HDL" is currently under very active investigation [1,7,13,15]. The current special issue of Current Medicinal Chemistry on “Current research, knowledge and controversies on high density lipoprotein (HDL)” has been completely dedicated to the most recent knowledge, and the current status of the mentioned above debate on the position of HDL-C as a cardiovascular biomarker. The Readers can, therefore, find papers on genetic determinants of HDL metabolism by Dr. Calabresi and her team [16], as well as on HDL metabolism regulation by Dr. Kardasis et al. [17]. The issue also includes a very important paper presenting the current expert opinions on subfraction and subpopulations of HDL cholesterol (by Dr. Rizzo et al.) [18] with the detailed information on the methods on analysis and reasons why there are still doubts on its role. Dr. Oravec et al. [19] present a paper on new hypothetical phenomena called atherogenic normolipidemia and non-atherogenic hyperlipidemia indicating that sometimes it might be necessary to widen the diagnostics and analyse the HDL and LDLsubfractions/subpopulations [20]. It also presents the current role of HDL cholesterol, both on endothelium and in CVD (by Dr. Madahian et al.) [21], in CHD patients (by Dr. Rysz et al.) [22], as well as in subjects with infection and cancer (by Dr. Katsiki et al.) [23]. Finally, Dr. Dragan and her colleagues present the scientifically confirmed methods to influence HDL functionality [24,25], and Drs. Duong and Nicholls describe the current state of research on new drugs for HDL disorders [26,27]. I do hope that that this special issue of Current Medicinal Chemistry will contribute to a better understanding of the properties and the role of HDL particles. Enjoy reading this issue!

Plasma high density lipoproteins (HDL) comprise a highly heterogeneous family of lipoprotein particles, with subclasses that can be separated and identified according to density, size, surface charge as well as shape and protein composition. There is evidence that these subclasses may differ in their functional properties. The individual plasma HDL cholesterol (HDL-C) level is generally taken as a snapshot of the steady-state concentration of all circulating HDL subclasses together, but this is insufficient to capture the structural and functional variation in HDL particles. HDL are continuously remodeled and metabolized in plasma and interstitial fluids, through the interaction with a large number of factors, including structural proteins, membrane transporters, enzymes, transfer proteins and receptors. Genetic variation in these factors can lead to essential changes in plasma HDL levels, and to remarkable changes in HDL particle density, size, surface charge, shape, and composition in lipids and apolipoproteins. This review discusses the impact of rare mutations and common variants in genes encoding factors involved in HDL remodeling and metabolism on plasma HDL-C levels and particle distribution. The study of the effects of human genetic variation in major players in HDL metabolism provides important clues on how individual factors modulate the formation, maturation, remodeling and catabolism of HDL.

Epidemiological studies have shown that low plasma levels of High Density Lipoprotein Cholesterol (HDL-C) are associated with an increased risk for myocardial infarction. These studies suggested that by increasing HDL-C levels one could reduce cardiovascular risk. However, emerging evidence from studies in animals and humans indicate that high levels of HDL-C are not sufficient to confer atheroprotection but that the functionality of the HDL particles is equally important. The picture is complicated further by the finding that HDL functionality is compromised in patients with chronic inflammatory diseases such as Coronary Artery Disease (CAD), diabetes and rheumatoid arthritis. Despite these obstacles, HDL raising is still a promising strategy for the reduction of CAD risk. Low HDL-C can be caused by inactivating mutations in apoA-I, ATP Binding Cassette Transporter A1 (ABCA1) or Lecithin-Cholesterol Acyl Transferase (LCAT) which affect HDL biogenesis and maturation whereas high HDL-C can be caused by mutations in Cholesteryl Ester Transfer Protein (CETP) or Scavenger receptor Class B Type I (SR-BI). Recent studies suggest that heterogeneity in HDL levels in the population is polygenic in origin. One approach to raise plasma HDL-C is to increase the rate of HDL biosynthesis by capitalizing on the mechanisms that control the transcription of genes that play key roles in HDL biogenesis. We review some of the genetic and non-genetic factors that affect plasma HDL levels and functions and discuss the mechanisms that regulate HDL metabolism at the level of gene transcription in the liver focusing on apoA-I, ABCA1 and apoM.

High-density lipoproteins (HDL) are classified as atheroprotective because they are involved in transport of cholesterol to the liver, known as “reverse cholesterol transport (RCT)” exerting antioxidant and anti-inflammatory activities. There is also evidence for cytoprotective, vasodilatory, antithrombotic, and anti-infectious activities for these lipoproteins. HDLs are known by structural, metabolic and biologic heterogeneity. Thus, different methods are able to distinguish several subclasses of HDL. Different separation techniques appear to support different HDL fractions as being atheroprotective or related with lower cardiovascular (CV) risk. However, HDL particles are not always protective. Modification of constituents of HDL particles (primarily in proteins and lipids) can lead to the decrease in their activity and induce proatherogenic properties, especially when isolated from patients with augmented systemic inflammation. According to available studies, it seems that HDL functionality may be a better therapeutic target than HDL cholesterol quantity; however, it is still disputable which subfractions are most beneficial. There is mounting evidence supporting HDL subclasses as an important biomarker to predict and/or reduce CV risk. In this review we discuss recent notices on atheroprotective and functional characteristic of different HDL subfractions. Also, we provide a brief overview of the different methods used by clinicians and researchers to separate HDL subfractions. Ongoing and future investigations will yield important new information if any given separation method might represent a ‘gold standard’, and which subfractions are reliable markers of CV risk and/or potential targets of novel, more focused, and effective therapies.

The electrophoretic separation of lipoproteins on polyacrylamide gels enables the quantification of nonatherogenic and atherogenic plasma lipoproteins including small dense low density lipoprotein (sdLDL) particles, which represent the atherogenic lipoprotein subpopulations in plasma. This methodology could help distinguish between nonatherogenic hyperlipidemia, normolipidemia with an atherogenic lipoprotein profile, non-atherogenic normolipidemia, and atherogenic hyperlipidemia. According to our pilot research of a normolipidemic population, the atherogenic lipoprotein profile might be present in about 6% of normolipidemic young healthy individuals. Therefore, if confirmed by other studies, it will be necessary to consider a different diagnostic approach and risk stratification for patients with atherogenic normolipidemia (as well as non-atherogenic hypercholesterolemia).

High density lipoprotein (HDL) has two important roles: a) it modulates inflammation, and, b) it promotes reverse cholesterol transport. HDLcholesterol levels are inversely correlated with the risk of cardiovascular events. The main component of HDL, apolipoprotein AI (apo AI), is largely responsible for reverse cholesterol transport through the macrophage ATPbinding cassette transporter ABCA1. Apo AI can be damaged by oxidative mechanisms, which render the protein less able to promote cholesterol efflux. HDL also contains a number of other proteins that are affected by the oxidative environment of the acutephase response. Modification of the protein components of HDL can convert it from an antiinflammatory to a pro inflammatory and dysfunctional particle. Small peptides that mimic some of the properties of apo AI have been shown in preclinical models to improve HDL function and reduce atherosclerosis without altering HDLcholesterol levels. Endothelium is the interface between the blood and the extra vascular environment regulating the traffic of vital molecules between the blood and tissues. Oxidative stress and excess levels of reactive oxygen species disrupt the normal function of endothelium. HDL and other antioxidant/anti-inflammatory systems prevent endothelial dysfunction and maintain the critical balance needed for normal vascular function.

Chronic kidney disease (CKD) is an emerging health hazard, connected to very high cardiovascular mortality due to accelerated atherosclerosis. Increased cardiovascular risk cannot be explained only by traditional risk factors. Patients with renal dysfunction have significant disturbances in lipoprotein metabolism and HDL in these patients becomes dysfunctional. It has been documented that in patients with CKD lower plasma level of HDL cholesterol and reduced ability of HDL to bind to ABCA1 are seen, which result in slowing down the reverse cholesterol transport and disturbances in HDL maturation due to decreased lecithin cholesterol ester transfer protein. Studies demonstrated that HDL of CKD patients loses its vasoprotective, antioxidative and anti-inflammatory properties and turns into a noxious particle which promotes endothelial dysfunction via stimulating superoxide production and limiting NO bioavailability. Alterations of HDL at the ‘molecular and functional level’ are also seen in renal transplant recipients even in those with excellent graft function.

Low levels of high-density lipoprotein cholesterol (HDL-C) have been associated with increased cardiovascular (CV) risk. These beneficial effects of HDL can be, at least partly, attributed to its anti-inflammatory, antithrombotic, antioxidant and endothelial-protective properties. However, the results of some clinical trials aiming at raising HDL-C levels are conflicting in terms of CV protection suggesting that alterations in HDL quality (and not only quantity) are involved in the atherosclerotic process. In this context, inflammation, oxidation, infection, hyperglycemia and activated platelets may modify HDL components, thus transforming HDL to a dysfunctional molecule with pro-atherogenic properties. Furthermore, some recent trials with HDL-raising drugs, such as niacin and torcetrapib, reported a lack of benefit in terms of vascular risk as well as adverse events including cancer and infections. In this narrative review, the findings of recent HDL clinical studies in relation to CV events as well as the associations of HDL with cancer and infections are discussed. The possible pathogenic mechanisms of these associations are also considered. The clinical implications of HDL function in treating patients at high CV risk remains to be established in future trials.

Many pharmacological and non-pharmacological strategies have been used to increase high-density lipoprotein- cholesterol (HDL-C) levels, but the results obtained have not been consistently associated with effective cardiovascular risk reduction. Therefore, research is now focused to improve HDL functionality, independent of HDL-C levels. The quality of HDL particles can vary considerably due to its heterogeneity caused by various lipids, proteins, vitamins, hormones and small RNAs that are associated with HDL. These components could act as potential HDL-related biomarkers, which may guide effective therapeutic interventions. Evaluation of HDL functionality seems to be more relevant, given the current evidence of the pleiotropic potentially atheroprotective functions of HDL. It is relevant to understand which HDL-related properties involved in its cardioprotective functions, in order to develop pharmacological and nonpharmacological therapies to improve HDL functionality.

For more than 20 years there has been increasing interest in the development of novel therapies to raise levels of high-density lipoprotein cholesterol (HDL-C). However, well publicized failures of recent clinical trials of agents that raise HDL-C levels have stimulated considerable controversy with regard to the potential clinical utility of this therapeutic target. A number of classes of agents are currently under investigation with variable effects on HDL quantity and quality. These will be reviewed.

Snakebites are a frequently neglected public health issue in tropical and subtropical countries. According to the World Health Organization, 5 million people are bitten annually including up to 2.5 million envenomations. Treatment with antivenom serum remains the only specific therapy for snakebite envenomation. However, it is heterologous and therefore liable to cause adverse reactions, such as early anaphylactic, pyrogenic and delayed reactions. In order to develop alternatives to the current therapy, researchers have been looking for natural products and plant extracts with antimyotoxic, anti-hemorrhagic and anti-inflammatory properties. Especially due to the role the physiopathological processes triggered by snake toxins, play in paralysis, bleeding disorders, kidney failure and tissue damage. Considering the fact that studies involving snake toxins and specific inhibitors, particularly on a molecular level, are the main key to understand neutralization mechanisms and to propose models or prototypes for an alternative therapy, this article presents efforts made by the scientific community in order to produce validated data regarding 87 compounds and plant extracts obtained from 79 species. These plants, which belong to 63 genera and 40 families, have been used by traditional medicine as alternatives or complements to the current serum therapy.

Statins are currently used as an effective cholesterol-lowering medication through inhibition of the mevalonate pathway, but recent studies show their potential for bone repair. The bone anabolic effects of statins have been largely attributed to their ability to enhance BMP-2 expression in osteoblast cells. In vitro studies have demonstrated that statins can increase the expression of osteogenic and angiogenic markers such as alkaline phosphatase, vascular endothelial growth factor, and osteocalcin in cells. In vivo, statins have been shown to promote significant new bone growth when injected systemically or locally in combination with a scaffold. The potential anabolic effects of statins on bone make them attractive candidates to support bone regeneration. Since the molecular pathways by which statins induce osteoblast differentiation are still unclear, further investigations are required to elucidate the detailed cellular signaling mechanisms involved to determine the type of statin, optimal dose and mode of delivery to effectively utilize their anabolic effect. This also warrants the development of novel vehicles to locally deliver statins for the desired time periods to support optimal tissue regeneration in vivo.

Endothelial dysfunction involving dysfunctional mitochondria precedes the development of cardiovascular diseases. This impairment results from an increase in reactive oxygen species, which leads to oxidative stress and a reduced bioavailability of nitric oxide. It has been demonstrated that oxidative stress and alterations in glucose and lipid homeostasis (e.g. hyperinsulinemia, hyperglycemia, insulin resistance and dyslipidemia) are linked to mitochondrial impairment and that all of them contribute to endothelial dysfunction. Anti-hyperlipidemic drugs such as statins, anti-hypertensive drugs and angiotensin receptor antagonists have been shown to exert protection through anti-oxidative stress mechanisms. Other substances with antioxidant properties, such as vitamins, are also capable of abolishing the oxidative stress associated with cardiometabolic diseases. However, the results obtained with general antioxidants in clinical trials are contradictory, perhaps due to the unspecific nature of the targets selected. This study correlates endothelial dysfunction and mitochondrial dysfunction and examines current research for the selective targeting of specific molecules (such as ·NO donors and antioxidants) to mitochondria with the aim of protecting the endothelium against oxidative stress in cardiovascular diseases.