Mendelian randomization studies on atherosclerotic cardiovascular disease: evidence and limitations

Epidemiological research has revealed a galaxy of biomarkers, such as genes, molecules or traits, which are associated with increased risk of atherosclerotic cardiovascular diseases(ASCVD). However, the etiological basis remains poorly characterized.Mendelian randomization(MR) involves the use of observational genetic data to ascertain the roles of disease-associated risk factors and, in particular, differentiate those reflecting the presence or severity of a disease from those contributing causally to a disease. Over the past decade, MR has evolved into a fruitful approach to clarifying the causal relation of a biomarker with ASCVD and to verifying potential therapeutic targets for ASCVD. In this review, we selected high-quality MR studies on ASCVD, examined the causal relationship of a series of biomarkers with ASCVD, and elucidated the role of MR in validating biomarkers as a therapeutic target by comparing the results from MR studies and randomized clinical trials(RCTs) for the treatment of ASCVD. The good agreement between the results derived by MR and RCTs suggests that MR could be performed as a screening process before novel drug development. However, when designing and interpreting a MR study, the assumptions and limitations inherent in this approach should be taken into account. Novel methodological developments, such as sensitivity analysis, will help to strengthen the validity of MR studies.     

A novel regulatory facet for hypertriglyceridemia: The role of microRNAs in the regulation of triglyceride-rich lipoprotein biosynthesis

Atherosclerotic cardiovascular disease (ASCVD) is one of the major leading global causes of death. Genetic and epidemiological studies strongly support the causal association between triacylglycerol-rich lipoproteins (TAGRL) and atherogenesis, even in statin-treated patients. Recent genetic evidence has clarified that variants in several key genes implicated in TAGRL metabolism are strongly linked to the increased ASCVD risk. There are several triacylglycerol-lowering agents; however, new therapeutic options are in development, among which are miRNA-based therapeutic approaches. MicroRNAs (miRNAs) are small non-coding RNAs (18–25 nucleotides) that negatively modulate gene expression through translational repression or degradation of target mRNAs, thereby reducing the levels of functional genes. MiRNAs play a crucial role in the development of hypertriglyceridemia as several miRNAs are dysregulated in both synthesis and clearance of TAGRL particles. MiRNA-based therapies in ASCVD have not yet been applied in human trials but are attractive. This review provides a concise overview of current interventions for hypertriglyceridemia and the development of novel miRNA and siRNA-based drugs. We summarize the miRNAs involved in the regulation of key genes in the TAGRLs synthesis pathway, which has gained attention as a novel target for therapeutic applications in CVD.     

The role of β-carotene and vitamin A in atherogenesis: Evidences from preclinical and clinical studies

Atherosclerotic cardiovascular disease (ASCVD) is the principal contributor to myocardial infarction, the leading cause of death worldwide. Epidemiological and mechanistic studies indicate that β-carotene and its vitamin A derivatives stimulate lipid catabolism in several tissues to reduce the incidence of obesity, but their roles within ASCVD are elusive. Herein, we review the mechanisms by which β-carotene and vitamin A modulate ASCVD. First, we summarize the current knowledge linking these nutrients with epidemiological studies and lipoprotein metabolism as one of the initiating factors of ASCVD. Next, we focus on different aspects of vitamin A metabolism in immune cells such as the mechanisms of carotenoid uptake and conversion to the vitamin A metabolite, retinoic acid. Lastly, we review the effects of retinoic acid on immuno-metabolism, differentiation, and function of macrophages and T cells, the two pillars of the innate and adaptive immune response in ASCVD, respectively.This article is part of a Special Issue entitled Carotenoids recent advances in cell and molecular biology edited by Johannes von Lintig and Loredana Quadro.     

H2O2 down-regulates SIRT7’s protective role of endothelial premature dysfunction via microRNA-335-5p

Endothelial senescence is believed to constitute the initial pathogenesis of the atherosclerotic cardiovascular disease (ASCVD). MicroRNA-335-5p (miR-335-5p) expression is significantly up-regulated in oxidative stress-induced endothelial cells (ECs). Sirtuin7 (SIRT7) is considered to prevent EC senescence, yet data on its response to ASCVD risk factors are limited. The present study analyzed the elevated levels of miR-335-5p and the decreased levels of SIRT7 in human umbilical vein endothelial cells (HUVECs), and found that high glucose, tumor necrosis factor-α (TNF-α), and H₂O₂ are the three contributing factors that induced cellular senescence. The current study also assessed premature endothelial senescence and decreased proliferation, adhesion, migration, and nitric oxide (NO) secretion in HUVECs with these risk factors together with SIRT7–siRNA transfection. It found that the miR-335-5p inhibitor attenuated the down-regulation of SIRT7 expression induced by oxidative stress in HUVECs, and SIRT7 overexpression exerts a rescue effect against miR-335-5p-induced endothelial dysfunction. Furthermore, the direct binding of miR-335-5p to SIRT7 was observed in human embryonic kidney cells 293T (HEK 293T). Therefore, it can be inferred that miR-335-5p down-regulates the expression of SIRT7 in human cells. Current findings may provide deeper insights into the underlying mechanisms of endothelial senescence and potential therapeutic targets of ASCVD as well as other age-related diseases.     

Ideal cardiovascular health and incidence of atherosclerotic cardiovascular disease among Chinese adults: the China-PAR project

Existing evidence on the relationship between cardiovascular health(CVH) metrics and cardiovascular disease(CVD) was primarily derived from western populations. We aimed to evaluate the benefits of ideal CVH metrics on preventing incident atherosclerotic CVD(ASCVD) in Chinese population. This study was conducted among 93,987 adults from the China-PAR project(Prediction for ASCVD Risk in China) who were followed up until 2015. Cox proportional hazard regression models were used to estimate the hazard ratios(HRs) and their corresponding 95% confidence intervals(CIs) of CVH metrics for the risk of ASCVD, including coronary heart disease(CHD), stroke and ASCVD death. We further estimated the population-attributable risk percentage(PAR%) of these metrics in relation to each outcome. We observed gradient inverse associations between the number of ideal CVH metrics and ASCVD incidence. Compared with participants having ≤2 ideal CVH metrics, the multivariable-adjusted HRs(95% CIs) of ASCVD for those with 3, 4, 5, 6 and 7 ideal CVH metrics were 0.83(0.74–0.93), 0.66(0.59–0.74), 0.55(0.48–0.61), 0.44(0.38–0.50) and 0.24(0.18–0.31), respectively(P for trend 0.0001). Approximately 62.1% of total ASCVD, 38.7% of CHD, 66.4% of stroke, and 60.5% of ASCVD death were attributable to not achieving all the seven ideal CVH metrics. After adjusting effects of ideal health factors, having four ideal health behaviors could independently bring adults health benefits in preventing 17.4% of ASCVD, 18.0% of CHD, 16.7% of stroke, and 10.1% of ASCVD death. Among all the seven CVH metrics, to keep with ideal blood pressure(BP) implied the largest public health gains against various ASCVD events(PAR% between 33.0% and 47.2%), while ideal diet was the metric most difficult to be achieved in the long term. Our study indicates that the more ideal CVH metrics adults have, the less ASCVD burden there is in China. Special efforts of health education and behavior modification should be made on keeping ideal BP and dietary habits in general Chinese population to prevent the epidemic of ASCVD.     

HDL cholesterol concentrations and risk of atherosclerotic cardiovascular disease – Insights from randomized clinical trials and human genetics

Through seven decades the inverse association between HDL cholesterol concentrations and risk of atherosclerotic cardiovascular disease (ASCVD) has been observed in case-control and prospective cohort studies. This robust inverse association fuelled the enthusiasm towards development of HDL cholesterol increasing drugs, exemplified by the cholesteryl ester transfer protein (CETP) inhibitor trials and the extended-release niacin HPS2-THRIVE trial. These HDL cholesterol increasing trials were launched without conclusive evidence from human genetics, and despite discrepant species dependent evidence from animal studies. Evidence from human genetics and from randomized clinical trials over the last 13 years now point in the direction that concentrations of HDL cholesterol, do not appear to be a viable future path to target therapeutically for prevention of ASCVD. A likely explanation for the strong observational association between low HDL cholesterol and high ASCVD risk is the concomitant inverse association between HDL cholesterol and atherogenic triglyceride-rich lipoproteins. The purpose of the present review is to bring HDL cholesterol increasing trials into a human genetics context exemplified by candidate gene studies of key players in HDL biogenesis as well as by HDL cholesterol related genome-wide association studies.     

Optimization of the cell seeding density and modeling of cell growth and metabolism using the modified Gompertz model for microencapsulated animal cell culture

Cell microencapsulation is one of the promising strategies for the in vitro production of proteins or in vivo delivery of therapeutic products. In order to design and fabricate the optimized microencapsulated cell system, the Gompertz model was applied and modified to describe the growth and metabolism of microencapsulated cell, including substrate consumption and product formation. The Gompertz model successfully described the cell growth kinetics and the modified Gompertz models fitted the substrate consumption and product formation well. It was demonstrated that the optimal initial cell seeding density was about 4-5 x 10(6) cells/mL of microcapsule, in terms of the maximum specific growth rate, the glucose consumption potential and the product formation potential calculated by the Gompertz and modified Gompertz models. Modeling of cell growth and metabolism in microcapsules provides a guideline for optimizing the culture of microencapsulated cells.     

Abdominal obesity negatively influences key metrics of reverse cholesterol transport

Cardiometabolic risk factors increase the risk of atherosclerotic cardiovascular disease (ASCVD), but whether these metabolic anomalies affect the anti-atherogenic function of reverse cholesterol transport (RCT) is not yet clearly known. The present study aimed to delineate if the function and maturation of high density lipoprotein (HDL) particles cross-sectionally associate with surrogate markers of ASCVD in a population comprising of different degree of cardiometabolic risk.We enrolled 131 subjects and characterized cardiometabolic risk based on the IDF criteria's for metabolic syndrome (MS). In this population, cholesterol efflux capacity (CEC), Lecithin–cholesterol acyltransferase (LCAT) and ApoA-1 glycation was associated with waist circumference, abdominal visceral fat (VFA) and abdominal subcutaneous fat. In multivariate analyses, VFA was identified as a critical contributor for low CEC and LCAT. When stratified into groups based on the presence of cardiometabolic risk factors, we found a prominent reduction in CEC and LCAT as a function of the progressive increase of cardiometabolic risk from 0–2, 0–3 to 0–4/5, whereas an increase in Pre-β-HDL and ApoA-1 glycation was observed between the lowest and highest risk groups.These findings confirm the connection between MS and its predisposing conditions to an impairment of atheroprotective efflux-promoting function of HDLs. Furthermore, we have identified the bona fide pathogenically contribution of abdominal obesity to profound alterations of key metrics of RCT.     

Determination of the surface charge of lipoproteins and its changes during lipid peroxidation

Surface potential of human plasma lipoproteins was studied by the use of positively charged spin probe. The calculated values of surface potential of high and low density lipoproteins appeared to be -29 +/- 1 and -16 +/- 1 respectively. It was shown that lipid peroxidation process induces an increase of surface potential of both high and low density lipoproteins. Probably, it is connected with the increase of the negative charge density on their surface. This fact can play an important role in pathogenesis of diseases with lipid metabolism and lipid peroxidation level disorders in plasma (atherosclerosis, ischemic heart disease etc.).     

Imaging myocardial metabolism

The prevalence of coronary artery disease and heart failure is increasing in modern industrialized countries, fueling the search for novel therapies. Because metabolism and function in the heart are inextricably linked, energy substrate metabolism has provided a potential target for novel therapies and the development of technologies to image myocardial metabolism has been crucial in establishing new therapeutic approaches. Nuclear imaging probes have been used to successfully evaluate aerobic fatty acid metabolism, anaerobic glucose metabolism, and oxidative metabolism and can be used for the accurate, sensitive, and physiological evaluation of therapeutic effects. More recently, with the advent of stem-cell technologies, imaging approaches have been employed to track the fate of stem cells and to monitor the success of these treatments. In the future, our ability to image myocardial metabolism is likely to assist the development of other new therapies to improve the function of the failing heart.     

Rocking cell metabolism: revised functions of the key glycolytic regulator PKM2 in cancer

Cancer cell metabolism is exemplified by high glucose consumption and lactate production. Pyruvate kinase (PK), which catalyzes the final step of glycolysis, has emerged as a potential regulator of this metabolic phenotype. The M2 isoform of PK (PKM2) is highly expressed in cancer cells. However, the mechanisms by which PKM2 coordinates high energy requirements with high anabolic activities to support cancer cell proliferation are still not completely understood. Current research has elucidated novel regulatory mechanisms for PKM2, contributing to its important role in cancer. This review summarizes the current understanding and explores future directions in the field, highlighting controversies regarding the activity and specificity of PKM2 in cancer. In light of this knowledge, the potential therapeutic implications and strategies are critically discussed.     

Alcoholic liver disease: new insights into mechanisms and preventative strategies

Alcoholic liver disease has a known aetiology but a complex pathogenesis. It is an extremely common disease with a high mortality, but the reason why only a relatively small proportion of heavy drinkers progress to advanced disease remains elusive. Accumulating evidence points towards an elaborate interplay between metabolism, inflammation and immunity in the development of steatosis, hepatitis and fibrosis. These complex pathways leading to liver injury offer many potential susceptibility loci, as well as sites for potential therapeutic intervention.     

Relationships between ecosystem metabolism, benthic macroinvertebrate densities, and environmental variables in a sub-arctic Alaskan river

Relationships between environmental variables, ecosystem metabolism, and benthos are not well understood in sub-arctic ecosystems. The goal of this study was to investigate environmental drivers of river ecosystem metabolism and macroinvertebrate density in a sub-arctic river. We estimated primary production and respiration rates, sampled benthic macroinvertebrates, and monitored light intensity, discharge rate, and nutrient concentrations in the Chena River, interior Alaska, over two summers. We employed Random Forests models to identify predictor variables for metabolism rates and benthic macroinvertebrate density and biomass, and calculated Spearman correlations between in-stream nutrient levels and metabolism rates. Models indicated that discharge and length of time between high water events were the most important factors measured for predicting metabolism rates. Discharge was the most important variable for predicting benthic macroinvertebrate density and biomass. Primary production rate peaked at intermediate discharge, respiration rate was lowest at the greatest time since last high water event, and benthic macroinvertebrate density was lowest at high discharge rates. The ratio of dissolved inorganic nitrogen to soluble reactive phosphorus ranged from 27:1 to 172:1. We found that discharge plays a key role in regulating stream ecosystem metabolism, but that low phosphorous levels also likely limit primary production in this sub-arctic stream.     

Antibody-based approaches in Alzheimer's research: safety, pharmacokinetics, metabolism, and analytical tools

High morbidity, enormous socioeconomic costs, and lack of specific treatments emphasize the importance of research on protective therapies against Alzheimer's disease. The efficacy of anti-amyloid immunization strategies has been demonstrated preclinically, prompting the design of clinical studies. However, the detailed mechanisms of action of therapeutic antibodies, especially their influence on the complex amyloid β peptide (Aβ) metabolism and various Aβ-equilibria present both within and outside the CNS, are far from being clear. Furthermore, physiological Aβ metabolism is poorly understood and the analytical tools to characterize and quantify treatment effects on Aβ metabolism are suboptimal. Thus, the design of immunization strategies with optimized benefit-to-risk ratios for patients is subjected to significant obstacles. Indeed, an active immunization trial with Aβ was discontinued because of severe adverse effects. Anti-Aβ immunization protocols designed to attain high blood levels of antibodies bear the potential to induce brain inflammation and/or hemorrhage, thus directing the biomedical research towards development of more predictable therapies for minimizing the risk of adverse effects. The focus of this review is to summarize current knowledge of Aβ metabolism under physiological and antibody-based therapeutic conditions and to introduce a promising approach, namely the passive immunization using antibody fragments, which are characterized by entirely different pharmacokinetic and pharmacodynamic properties compared with conventional monoclonal antibodies.     

Polyamine homoeostasis as a drug target in pathogenic protozoa: peculiarities and possibilities

New drugs are urgently needed for the treatment of tropical and subtropical parasitic diseases, such as African sleeping sickness, Chagas' disease, leishmaniasis and malaria. Enzymes in polyamine biosynthesis and thiol metabolism, as well as polyamine transporters, are potential drug targets within these organisms. In the present review, the current knowledge of unique properties of polyamine metabolism in these parasites is outlined. These properties include prozyme regulation of AdoMetDC (S-adenosylmethionine decarboxylase) activity in trypanosomatids, co-expression of ODC (ornithine decarboxylase) and AdoMetDC activities in a single protein in plasmodia, and formation of trypanothione, a unique compound linking polyamine and thiol metabolism in trypanosomatids. Particularly interesting features within polyamine metabolism in these parasites are highlighted for their potential in selective therapeutic strategies.     

Therapeutic potentials and modulatory mechanisms of fatty acids in bone

Bone metabolism is a lifelong process that includes bone formation and resorption. Osteoblasts and osteoclasts are the predominant cell types associated with bone metabolism, which is facilitated by other cells such as bone marrow mesenchymal stem cells (BMMSCs), osteocytes and chondrocytes. As an important component in our daily diet, fatty acids are mainly categorized as long‐chain fatty acids including polyunsaturated fatty acids (LCPUFAs), monounsaturated fatty acids (LCMUFAs), saturated fatty acids (LCSFAs), medium‐/short‐chain fatty acids (MCFAs/SCFAs) as well as their metabolites. Fatty acids are closely associated with bone metabolism and associated bone disorders. In this review, we summarized the important roles and potential therapeutic implications of fatty acids in multiple bone disorders, reviewed the diverse range of critical effects displayed by fatty acids on bone metabolism, and elucidated their modulatory roles and mechanisms on specific bone cell types. The evidence supporting close implications of fatty acids in bone metabolism and disorders suggests fatty acids as potential therapeutic and nutritional agents for the treatment and prevention of metabolic bone diseases.     

Protein arginine methylation promotes therapeutic resistance in human pancreatic cancer

Pancreatic cancer is a lethal disease with limited treatment options for cure. A high degree of intrinsic and acquired therapeutic resistance may result from cellular alterations in genes and proteins involved in drug transportation and metabolism, or from the influences of cancer microenvironment. Mechanistic basis for therapeutic resistance remains unclear and should profoundly impact our ability to understand pancreatic cancer pathogenesis and its effective clinical management. Recent evidences have indicated the importance of epigenetic changes in pancreatic cancer, including posttranslational modifications of proteins. We will review new knowledge on protein arginine methylation and its consequential contribution to therapeutic resistance of pancreatic cancer, underlying molecular mechanism, and clinical application of potential strategies of its reversal.     

Epigenetic developmental programs and adipogenesis

Psychotropic agents are notorious for their ability to increase fat mass in psychiatric patients. The two determinants of fat mass are the production of newly differentiated adipocytes (adipogenesis), and the volume of lipid accumulation. Epigenetic programs have a prominent role in cell fate commitments and differentiation required for adipogenesis. In parallel, epigenetic effects on energy metabolism are well supported by several genetic models. Consequently, a variety of psychotropics, often prescribed in combinations and for long periods, may utilize a common epigenetic effector path causing an increase in adipogenesis or reduction in energy metabolism. In particular, the recent discovery that G protein coupled signaling cascades can directly modify epigenetic regulatory enzymes implicates surface receptor activity by psychotropic medications. The potential therapeutic implications are also suggested by the effects of the clinically approved antidepressant tranylcypromine, also a histone demethylase inhibitor, which has impressive therapeutic effects on metabolism in the obese phenotype.