• Biomolecule
• Circulating miRNAs
• Exosome
• IVF
• Reproductive health

• Humans
• Circulating MicroRNA/metabolism
• Circulating MicroRNA/blood
• Circulating MicroRNA/genetics
• Female
• Male
• Body Fluids/metabolism
• Reproduction/physiology
• Biomarkers/blood
• Animals
• MicroRNAs/blood
• Pregnancy

• DST, India DST, India

• Ectosomes
• Exomeres
• Exosomes
• Extracellular vesicles
• Microvesicles
• Non-vesicular extracellular nanoparticles
• Supermeres

• Extracellular Vesicles/metabolism
• Humans
• Nanoparticles/chemistry
• Animals
• Cell Communication

• U2CCA233291 NCI NIH HHS
• Nicholas Tierney GI Cancer Memorial Fund

• CVD
• HDL
• aging
• diet
• inflammation
• lipoproteins
• oxidative stress

• (grant number #PJT162366) CIHR

• accelerator mass spectrometry
• fluorescent imaging
• isopycnic centrifugation
• lipoproteins
• α-tocopherol tracer analysis

• Male
• Female
• Humans
• Lipoproteins
• alpha-Tocopherol
• Triglycerides
• Carbon
• Mass Spectrometry
• Lipoproteins, VLDL
• Lipoproteins, LDL

• P41 RR013461 NCRR NIH HHS
• R24 GM137748 NIGMS NIH HHS

• Aterosclerosis
• Atherosclerosis
• Cardiovascular disease
• Enfermedad cardiovascular
• HDL
• Terapia
• Therapy

• Humans
• Cardiovascular Diseases/etiology
• Cardiovascular Diseases/prevention & control
• Cardiovascular Diseases/drug therapy
• Cholesterol Ester Transfer Proteins/therapeutic use
• Cholesterol/metabolism
• Atherosclerosis/etiology
• Atherosclerosis/drug therapy
• Lipoproteins, HDL/metabolism
• Cholesterol, HDL

• gene regulation
• high-density lipoproteins
• microRNA biogenesis
• microRNA secretion
• signal transduction

• Computational biology
• Familial hypercholesterolemia
• Gain-of-function mutation
• High-density lipoproteins
• Low-density lipoprotein receptor
• Proprotein convertase subtilisin kexin type 9

• Humans
• Proprotein Convertase 9/genetics
• Lipoproteins, HDL/genetics
• Proteomics
• Hyperlipoproteinemia Type II/genetics
• Structure-Activity Relationship
• Receptors, LDL/genetics
• Mutation

• apolipoproteins
• extracellular RNA
• intercellular communication
• lipoproteins
• macrophage

• Apolipoprotein
• Cholesterol accumulation
• Cholesterol metabolism
• Chronic kidney disease
• Lipotoxicity

• Atherosclerosis
• Cholesterol/metabolism
• Diabetes Mellitus, Type 2
• Female
• Humans
• Lipoproteins/metabolism
• Male
• Non-alcoholic Fatty Liver Disease
• Renal Insufficiency, Chronic/therapy

• P30 DK020541 NIDDK NIH HHS
• R56 HL137912 NHLBI NIH HHS

• Atherosclerosis
• Fatty acids
• High-density lipoprotein
• Lecithin cholesterol acyl transferase
• Phospholipids

• Acute Coronary Syndrome/blood
• Acute Coronary Syndrome/ethnology
• Adult
• Asian People
• Female
• Humans
• India
• Lipoproteins, HDL/blood
• Male
• Middle Aged
• Phospholipids/blood
• Proteome/metabolism

• Mediterranean diet
• calorie restriction
• high-density lipoprotein
• physical activity
• randomized controlled trial

• Aged
• Diet, Mediterranean
• Exercise
• Female
• Humans
• Life Style
• Lipoproteins, HDL/metabolism
• Lipoproteins, HDL/physiology
• Male
• Metabolic Syndrome/diet therapy
• Metabolic Syndrome/metabolism
• Middle Aged
• Triglycerides/metabolism

• Animals
• Cardiovascular Diseases/etiology
• Cardiovascular Diseases/metabolism
• Fatty Acids/metabolism
• Humans
• Lipoproteins/metabolism
• Lipoproteins, HDL/metabolism
• Lipoproteins, LDL/metabolism
• Renal Insufficiency, Chronic/complications
• Renal Insufficiency, Chronic/metabolism

• Angiogenesis
• Gynecological cancers
• Non-coding RNAs

• Cholesterol efflux
• Coronary microenvironment
• NSTEMI
• Preβ-HDL

• Cardiovascular risk factors
• Cholesterol homeostasis
• Lipoproteins
• Neurological diseases
• Oxysterols
• miRNAs

• Animals
• Brain/metabolism
• Cardiovascular Diseases/metabolism
• Cholesterol/metabolism
• Homeostasis
• Humans
• Neurodegenerative Diseases/metabolism

High Density Lipoprotein (HDL) particles, beyond serving as lipid transporters and playing a key role in reverse cholesterol transport, carry a highly variable number of proteins, micro-RNAs, vitamins, and hormones, which endow them with the ability to mediate a plethora of cellular and molecular mechanisms that promote cardiovascular health. It is becoming increasingly evident, however, that the presence of cardiovascular risk factors and co-morbidities alters HDLs cargo and protective functions. This concept has led to the notion that metrics other than HDL-cholesterol levels, such as HDL functionality and composition, may better capture HDL cardiovascular protection. On the other hand, the potential of HDL as natural delivery carriers has also fostered the design of engineered HDL-mimetics aiming to improve HDL efficacy or as drug-delivery agents with therapeutic potential. In this paper, we first provide an overview of the molecules known to be transported by HDL particles and mainly discuss their functions in the cardiovascular system. Second, we describe the impact of cardiovascular risk factors and co-morbidities on HDL remodeling. Finally, we review the currently developed HDL-based approaches.

• HDL
• cardiovascular disease
• cardiovascular risk factors
• engineered HDL-mimetics

MicroRNAs (miRNAs) are a group of small non-coding RNAs with approximately 19–25 nucleotides that are involved in regulating a range of developmental and physiological processes. Non-exosomal circulating and exosomal miRNAs have also been proposed to be useful in diagnostics as biomarkers for diseases and different types of cancer. In this review, the quantity of miRNAs and of reliable experimental data analyses of miRNAs that come from exosomal and non-exosomal sources are discussed from the perspective of their use as biomarkers for cancer and other diseases, including viral infections, nervous system disorders, cardiovascular disorders, and diabetes. We summarize other research findings regarding the use of miRNA from these two sources as biomarkers in diagnostics and clinical use. The challenges in using miRNA from these two sources in cancer and disease diagnostics are evaluated and discussed. Validation of specific miRNA signatures as biomarkers is a critical milestone in diagnostics.

• biomarker
• body fluid
• exosome
• miRNA
• non-exosomal

Extracellular microRNAs (miRNAs) are a new class of biomarkers for cellular phenotypes and disease, and are bioactive signals within intercellular communication networks. Previously, we reported that miRNAs are secreted from macrophage to high-density lipoproteins (HDL) and delivered to recipient cells to regulate gene expression. Despite the potential importance of HDL-miRNAs, regulation of HDL-miRNA export from cells has not been fully studied. Here, we report that pancreatic islets and beta cells abundantly export miR-375-3p to HDL and this process is inhibited by cellular mechanisms that promote insulin secretion. Small RNA sequencing and PCR approaches were used to quantify beta cell miRNA export to HDL. Strikingly, high glucose conditions were found to inhibit HDL-miR-375-3p export, which was dependent on extracellular calcium. Likewise, stimulation of cAMP was found to repress HDL-miR-375-3p export. Furthermore, we found that beta cell ATP-sensitive potassium channel (K_ATP) channels are required for HDL-miRNA export as chemical inhibition (tolbutamide) and global genetic knockout (Abcc8^−/−) approaches inhibited HDL-miR-375-3p export. This process is not likely associated with cholesterol flux, as gain-of-function and loss-of-function studies for cholesterol transporters failed to alter HDL-miR-375-3p export. In conclusion, results support that pancreatic beta cells export miR-375-3p to HDL and this process is inversely regulated to insulin secretion.

• antioxidant
• peroxiredoxin6
• senescence
• type 2 diabetes mellitus

• Animals
• Antioxidants/metabolism
• Chronic Disease
• Humans
• Noncommunicable Diseases
• Peroxiredoxin VI/metabolism

• Gestational age
• HDL
• LDL
• pregnancy
• preterm labor

• Editorials
• atherosclerosis
• cholesterol esters
• cholesterol, HDL
• cholesterol, LDL
• lecithin:cholesterol acyltransferase deficiency

• Atherosclerosis
• Cholesterol, LDL
• Humans
• Lecithin Cholesterol Acyltransferase Deficiency
• Lecithins
• Phosphatidylcholine-Sterol O-Acyltransferase
• Sterol O-Acyltransferase

• P01 HL059407 NHLBI NIH HHS
• R01 HL055323 NHLBI NIH HHS

Peptides mimicking the major protein of highdensity lipoprotein (HDL), apolipoprotein A-I (apoA-I), are promising therapeutics for cardiovascular diseases. Similar to apoA-I, their atheroprotective property is attributed to their ability to form discoidal HDL-like particles by extracting cellular cholesterol and phospholipids from lipid microdomains created by the ABCA1 transporter in a process called cholesterol efflux. The structural features of peptides that enable cholesterol efflux are not well understood. Herein, four synthetic amphipathic peptides denoted ELK, which only contain Glu, Leu, Lys, and sometimes Ala, and which have a wide range of net charges and hydrophobicities, were examined for cholesterol efflux. Experiments show that ELKs with a net neutral charge and a hydrophobic face that subtends an angle of at least 140° are optimal for cholesterol efflux. All-atom molecular dynamics simulations show that peptides that are effective in promoting cholesterol efflux stabilize HDL nanodiscs formed by these peptides by the orderly covering of the hydrophobic acyl chains on the edge of the disc. In contrast to apoA-I, which forms an anti-parallel double belt around the HDL, active peptides assemble in a mostly anti-parallel “picket fence” arrangement. These results shed light on the efflux ability of apoA-I mimetics and inform the future design of such therapeutics.

• Cardiovascular disease
• GlycA
• Lipoprotein particles
• Nuclear magnetic resonance spectroscopy

Although drug trials with niacin and cholesteryl ester transfer protein inhibitors that substantially increase high-density lipoprotein-cholesterol (HDL-C) failed to reduce the risk of coronary heart disease, HDL protection of the cardiovascular system cannot be easily denied. Hence, it may be HDL subfractions that are responsible for the long-held and consistent cardioprotective association of HDL. Arterial stiffness has been increasingly recognized as a strong predictor of subclinical vascular disease, atherosclerotic disease, and cardiovascular mortality. As the association of HDL subfractions and arterial stiffness is not well characterized, we aimed to determine the relations between these two entities in a community-based longitudinal Chinese population sample.

We evaluated the associations of plasma HDL2-C and HDL3-C subfractions with arterial stiffness measured using carotid-femoral pulse wave velocity (cf-PWV) and then multivariate logistic regression in 1447 subjects (mean age 61.3 years) from a community-based population in Beijing, China.

After a median follow-up of 4.8 years, Pearson’s correlation analysis revealed that HDL3-C was negatively associated with follow-up cf-PWV (r = −0.114; P = 0.001), and there was no correlation between HDL2-C and follow-up cf-PWV (r = −0.045; P = 0.181). In the multivariate logistic regression analysis, each standard deviation (SD) increase in HDL3-C was associated with a 1.490-increased likelihood of the presence of follow-up cf-PWV [odds ratio (per SD increase in HDL3-C) 1.490; 95% confidence interval 1.021–1.470; P = 0.039), whereas there was no relation between HDL2-C and follow-up cf-PWV.

HDL3-C subfractions were significantly and inversely associated with arterial stiffness, suggesting that HDL subfractions are likely more important than HDL-C in preventing cardiovascular disease.

• HDL3-C
• arterial stiffness
• prospective study

Supplemental Digital Content is available in the text.

Early detection of adverse effects of novel therapies and understanding of their mechanisms could improve the safety and efficiency of drug development. We have retrospectively applied large-scale proteomics to blood samples from ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), a trial of torcetrapib (a cholesterol ester transfer protein inhibitor), that involved 15 067 participants at high cardiovascular risk. ILLUMINATE was terminated at a median of 550 days because of significant absolute increases of 1.2% in cardiovascular events and 0.4% in mortality with torcetrapib. The aims of our analysis were to determine whether a proteomic analysis might reveal biological mechanisms responsible for these harmful effects and whether harmful effects of torcetrapib could have been detected early in the ILLUMINATE trial with proteomics.

A nested case-control analysis of paired plasma samples at baseline and at 3 months was performed in 249 participants assigned to torcetrapib plus atorvastatin and 223 participants assigned to atorvastatin only. Within each treatment arm, cases with events were matched to controls 1:1. Main outcomes were a survey of 1129 proteins for discovery of biological pathways altered by torcetrapib and a 9-protein risk score validated to predict myocardial infarction, stroke, heart failure, or death.

Plasma concentrations of 200 proteins changed significantly with torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in endocrine systems, including in aldosterone function and glycemic control. At baseline, 9-protein risk scores were similar in the 2 treatment arms and higher in participants with subsequent events. At 3 months, the absolute 9-protein derived risk increased in the torcetrapib plus atorvastatin arm compared with the atorvastatin-only arm by 1.08% (P=0.0004). Thirty-seven proteins changed in the direction of increased risk of 49 proteins previously associated with cardiovascular and mortality risk.

Heretofore unknown effects of torcetrapib were revealed in immune and inflammatory functions. A protein-based risk score predicted harm from torcetrapib within just 3 months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients.

URL: https://www.clinicaltrials.gov. Unique identifier: NCT00134264.

• aptamers
• biomarkers
• peptides
• precision medicine
• prescription drugs
• proteins
• proteomics

• epidermal growth factor receptor
• gene transfer
• hepatectomy
• microarray
• proliferation
• steatosis

• Animals
• Apoptosis/genetics
• Blotting, Western
• Diet, High-Fat
• ErbB Receptors/genetics
• Gene Expression Profiling
• Hepatectomy
• Liver/metabolism
• Liver/pathology
• Liver/surgery
• Liver Regeneration/genetics
• Mice
• Mice, Inbred C57BL
• Mitosis/genetics
• Non-alcoholic Fatty Liver Disease/genetics
• Non-alcoholic Fatty Liver Disease/metabolism
• Non-alcoholic Fatty Liver Disease/pathology
• Obesity/metabolism
• Survival Rate

• R01 GM092758 NIGMS NIH HHS
• R01 CA194593 NCI NIH HHS
• R01 CA122596 NCI NIH HHS
• P30 DK097512 NIDDK NIH HHS
• R01 DK096167 NIDDK NIH HHS

• Atherosclerosis
• Cholesterol
• Endocrinology
• Lipoproteins
• Metabolism

• Apolipoprotein A-I
• Cholesterol
• Cytokines
• HDL proteome
• Lipoprotein sizing
• low birthweight
• preterm

High-density lipoproteins (HDLs) are complex protein and lipid assemblies whose composition is known to change in diverse pathological situations. Analysis of the HDL proteome can thus provide insight into the main mechanisms underlying abdominal aortic aneurysm (AAA) and potentially detect novel systemic biomarkers. We performed a multiplexed quantitative proteomics analysis of HDLs isolated from plasma of AAA patients (N = 14) and control study participants (N = 7). Validation was performed by western-blot (HDL), immunohistochemistry (tissue), and ELISA (plasma). HDL from AAA patients showed elevated expression of peroxiredoxin-6 (PRDX6), HLA class I histocompatibility antigen (HLA-I), retinol-binding protein 4, and paraoxonase/arylesterase 1 (PON1), whereas α-2 macroglobulin and C4b-binding protein were decreased. The main pathways associated with HDL alterations in AAA were oxidative stress and immune-inflammatory responses. In AAA tissue, PRDX6 colocalized with neutrophils, vascular smooth muscle cells, and lipid oxidation. Moreover, plasma PRDX6 was higher in AAA (N = 47) than in controls (N = 27), reflecting increased systemic oxidative stress. Finally, a positive correlation was recorded between PRDX6 and AAA diameter. The analysis of the HDL proteome demonstrates that redox imbalance is a major mechanism in AAA, identifying the antioxidant PRDX6 as a novel systemic biomarker of AAA.

• Cardiovascular disease
• Coronary artery disease
• Review
• Risk factors
• miRNA

• Animals
• Biomarkers/blood
• Cardiovascular Diseases/blood
• Cardiovascular Diseases/diagnosis
• Cardiovascular Diseases/genetics
• Cell Communication
• Cholesterol/blood
• Coronary Artery Disease/blood
• Coronary Artery Disease/genetics
• Homeostasis
• Humans
• Hyperlipidemias/complications
• Hypertension/complications
• Lipoproteins, HDL/metabolism
• Lipoproteins, LDL/metabolism
• Mice
• MicroRNAs/genetics
• Obesity/complications
• Risk Factors
• Smoking/adverse effects
• Nicotiana
• Treatment Outcome

• R01 GM113995 NIGMS NIH HHS
• R01 GM027673 NIGMS NIH HHS
• UL1 TR000062 NCATS NIH HHS
• KL2 TR000060 NCATS NIH HHS
• UL1 TR001450 NCATS NIH HHS
• T32 HL007260 NHLBI NIH HHS

• apolipoprotein A I
• high-density lipoprotein
• inflammasome
• interleukin-1β

• Animals
• Anti-Inflammatory Agents/therapeutic use
• Atherosclerosis/drug therapy
• Atherosclerosis/immunology
• Cell Line
• Cholesterol/immunology
• Female
• Humans
• Inflammasomes/metabolism
• Inflammation/drug therapy
• Inflammation/immunology
• Interleukin-1beta/metabolism
• Lipoproteins, HDL/therapeutic use
• Macrophages/drug effects
• Macrophages/immunology
• Mice
• Mice, Inbred C57BL
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism

• Cardiovascular risk
• Lipids
• Outcomes

• Antisense oligonucleotides
• HDL
• Lipoproteins
• Locked-nucleic acids
• MicroRNAs

High density lipoproteins (HDLs) are thought to be atheroprotective and to reduce the risk of cardiovascular disease (CVD). Besides their antioxidant, antithrombotic, anti-inflammatory, anti-apoptotic properties in the vasculature, HDLs also improve glucose metabolism in skeletal muscle.

Herein, we review the functional role of HDLs to improve metabolic disorders, especially those involving insulin resistance and to induce regression of CVD with a particular focus on current pharmacological treatment options as well as lifestyle interventions, particularly exercise.

Functional properties of HDLs continue to be considered important mediators to reverse metabolic dysfunction and to regress atherosclerotic cardiovascular disease. Lifestyle changes are often recommended to reduce the risk of CVD, with exercise being one of the most important of these. Understanding how exercise improves HDL function will likely lead to new approaches to battle the expanding burden of obesity and the metabolic syndrome.

• Atherosclerotic plaque regression
• Glucose homeostasis
• HDL function
• High density lipoprotein (HDL)
• Metabolic disease
• Physical activity

• Extracellular microRNA
• HDL
• Lipoproteins
• microRNA

• HDL
• Metabolic syndrome
• Obesity
• Sphingomyelin
• Weight loss

• High-density lipoprotein cholesterol
• coronary heart disease
• primary prevention

• Adult
• Black or African American
• Aged
• Biomarkers/blood
• Centrifugation, Density Gradient
• Chi-Square Distribution
• Cholesterol, HDL/blood
• Cholesterol, HDL/classification
• Coronary Disease/blood
• Coronary Disease/diagnosis
• Coronary Disease/epidemiology
• Coronary Disease/prevention & control
• Dyslipidemias/blood
• Dyslipidemias/diagnosis
• Dyslipidemias/epidemiology
• Dyslipidemias/therapy
• Female
• Humans
• Incidence
• Male
• Massachusetts/epidemiology
• Middle Aged
• Mississippi/epidemiology
• Multivariate Analysis
• Particle Size
• Primary Prevention
• Proportional Hazards Models
• Risk Factors
• White People

• T32HL007227 NHLBI NIH HHS
• N01-HC-25195-06 NHLBI NIH HHS
• T32 HL007024 NHLBI NIH HHS
• T32 HL007227 NHLBI NIH HHS
• N01HC25195 NHLBI NIH HHS
• T32HL07024 NHLBI NIH HHS

• Adult
• Arsenic/toxicity
• Cardiovascular Diseases/blood
• Cross-Sectional Studies
• Diabetes Mellitus/blood
• Female
• Humans
• Linear Models
• Male
• Mexico
• Middle Aged
• Water Pollutants, Chemical/toxicity

• P30 ES010126 NIEHS NIH HHS
• R01ES015326 NIEHS NIH HHS
• 3R01ES015326 NIEHS NIH HHS
• P30 DK056350 NIDDK NIH HHS
• DK056350 NIDDK NIH HHS
• 001 World Health Organization
• P2C HD050924 NICHD NIH HHS
• P30ES010126 NIEHS NIH HHS
• R01 ES015326 NIEHS NIH HHS
• P42 ES005948 NIEHS NIH HHS