Unravelling molecular mechanisms in atherosclerosis using cellular models and omics technologies.

Despite the discovery and prevalent clinical use of potent lipid-lowering therapies, including statins and PCSK9 inhibitors, cardiovascular diseases (CVD) caused by atherosclerosis remain a large unmet clinical need, accounting for frequent deaths worldwide. The pathogenesis of atherosclerosis is a complex process underlying the presence of modifiable and non-modifiable risk factors affecting several cell types including endothelial cells (ECs), monocytes/macrophages, smooth muscle cells (SMCs) and T cells. Heterogeneous composition of the plaque and its morphology could lead to rupture or erosion causing thrombosis, even a sudden death.

Bioactive Compounds Formulated in Phytosomes Administered as Complementary Therapy for Metabolic Disorders.

Metabolic disorders (MDs), including dyslipidemia, non-alcoholic fatty liver disease, diabetes mellitus, obesity and cardiovascular diseases are a significant threat to human health, despite the many therapies developed for their treatment. Different classes of bioactive compounds, such as polyphenols, flavonoids, alkaloids, and triterpenes have shown therapeutic potential in ameliorating various disorders. Most of these compounds present low bioavailability when administered orally, being rapidly metabolized in the digestive tract and liver which makes their metabolites less effective.

Elevated Levels of Circulating lncRNAs LIPCAR and MALAT1 Predict an Unfavorable Outcome in Acute Coronary Syndrome Patients.

Coronary artery disease (CAD) is a leading cause of mortality worldwide. In this study, we aimed to assess the potential of plasma long non-coding RNAs (lncRNAs) LIPCAR and MALAT1 and microRNAs (miRNAs) miR-142-3p and miR-155-5p to discriminate unstable CAD patients from stable ones. 23 stable angina (SA), 21 unstable angina (UA), and 50 ST-segment elevation myocardial infarction (STEMI) patients were enrolled; their plasma was collected.

Oscillating Glucose Induces the Increase in Inflammatory Stress through Ninjurin-1 Up-Regulation and Stimulation of Transport Proteins in Human Endothelial Cells.

Clinical data implicate fluctuations of high levels of plasma glucose in cardiovascular diseases. Endothelial cells (EC) are the first cells of the vessel wall exposed to them. Our aim was to evaluate the effects of oscillating glucose (OG) on EC function and to decipher new molecular mechanisms involved.

Mitochondrial DNA Together with miR-142-3p in Plasma Can Predict Unfavorable Outcomes in Patients after Acute Myocardial Infarction.

Myocardial infarction is one of the leading causes of death worldwide, despite numerous efforts to find efficient prognostic biomarkers and treatment targets. In the present study, we aimed to assess the potential of six microRNAs known to be involved in cardiovascular diseases, cell-free DNA (cfDNA), and mitochondrial DNA (mtDNA) circulating in plasma to be used as prognostic tools for the occurrence of unfavorable outcomes such as major adverse cardiovascular events (MACE) after acute ST-segment elevation myocardial infarction (STEMI). Fifty STEMI patients were enrolled and monitored for 6 months for the occurrence of MACE.

miR-146a-5p, miR-223-3p and miR-142-3p as Potential Predictors of Major Adverse Cardiac Events in Young Patients with Acute ST Elevation Myocardial Infarction-Added Value over Left Ventricular Myocardial Work Indices.

Acute ST elevation myocardial infarction (STEMI) remains a leading cause of morbidity and mortality worldwide despite continuous advances in diagnostic, prognostic and therapeutic methods. Myocardial work (MW) indices and miRNAs have both emerged as potential prognostic markers in acute coronary syndromes in recent years. In this study we aim to assess the prognostic role of myocardial work indices and of a group of miRNAs in young patients with STEMI.

CRISPR/dCas9 Transcriptional Activation of Endogenous Apolipoprotein AI and Paraoxonase 1 in Enterocytes Alleviates Endothelial Cell Dysfunction.

Atherosclerosis is the main cause of cardiovascular diseases with high prevalence worldwide. A promising therapeutic strategy to reverse atherosclerotic process is to improve the athero-protective potential of high-density lipoproteins (HDL). Since the small intestine is a source of HDL, we aimed to activate transcription of the endogenous HDL major proteins, apolipoprotein AI (ApoAI) and paraoxonase 1 (PON1), in enterocytes, and to evaluate their potential to correct the pro-inflammatory status of endothelial cells (EC).

Clusterin, paraoxonase 1, and myeloperoxidase alterations induce high-density lipoproteins dysfunction and contribute to peripheral artery disease; aggravation by type 2 diabetes mellitus.

Peripheral artery disease (PAD) is an atherosclerotic disorder affecting arteries of the lower limbs, the major risk factors including dyslipidemia and diabetes mellitus (DM). We aimed to identify alterations of the proteins in high-density lipoproteins (HDL) associated with HDL dysfunction in PAD patients. HDL and HDL were isolated from plasma of PAD patients with/without DM (PAD-DM/PAD) and healthy subjects (N).

MiR-223-3p levels in the plasma and atherosclerotic plaques are increased in aged patients with carotid artery stenosis; association with HDL-related proteins.

Background: Cardiovascular diseases are still the main cause of death worldwide. Our aim was to analyse the link between miR-223-3p levels, dysfunctional HDL and the age of patients with carotid artery stenosis (CAS).

Methods And Results: Thirty-two CAS patients enrolled for endarterectomy were divided in 2 groups: aged over 65 years (n = 19) and under 65 years (n = 13).

Aggregated LDL turn human macrophages into foam cells and induce mitochondrial dysfunction without triggering oxidative or endoplasmic reticulum stress.

Uptake of modified lipoproteins by macrophages turns them into foam cells, the hallmark of the atherosclerotic plaque. The initiation and progression of atherosclerosis have been associated with mitochondrial dysfunction. It is known that aggregated low-density lipoproteins (agLDL) induce massive cholesterol accumulation in macrophages in contrast with native LDL (nLDL) and oxidized LDL (oxLDL).

Endothelial Dysfunction in Diabetes Is Aggravated by Glycated Lipoproteins; Novel Molecular Therapies.

Diabetes and its vascular complications affect an increasing number of people. This disease of epidemic proportion nowadays involves abnormalities of large and small blood vessels, all commencing with alterations of the endothelial cell (EC) functions. Cardiovascular diseases are a major cause of death and disability among diabetic patients.

Increased miR-142 Levels in Plasma and Atherosclerotic Plaques from Peripheral Artery Disease Patients with Post-Surgery Cardiovascular Events.

There is an intensive effort to identify biomarkers to predict cardiovascular disease evolution. We aimed to determine the potential of microRNAs to predict the appearance of cardiovascular events (CVEs) in patients with peripheral artery disease (PAD) following femoral artery bypass surgery. Forty-seven PAD patients were enrolled and divided into two groups, without CVEs ( = 35) and with CVEs ( = 12), during 1 year follow-up.

Regulation of microRNAs in high-fat diet induced hyperlipidemic hamsters.

Dyslipidemia is a documented risk factor for cardiovascular diseases and other metabolic disorders. Therefore, the analysis of hyperlipidemia (HL)-related miRNAs is a potential approach for achieving new prognostic markers in lipid-metabolism related diseases. We aimed to analyze specific distribution of miRNAs in different tissues from HL animals.

Phenolic Compounds Exerting Lipid-Regulatory, Anti-Inflammatory and Epigenetic Effects as Complementary Treatments in Cardiovascular Diseases.

Atherosclerosis is the main process behind cardiovascular diseases (CVD), maladies which continue to be responsible for up to 70% of death worldwide. Despite the ongoing development of new and potent drugs, their incomplete efficacy, partial intolerance and numerous side effects make the search for new alternatives worthwhile. The focus of the scientific world turned to the potential of natural active compounds to prevent and treat CVD.

Ninjurin-1 upregulated by TNFα receptor 1 stimulates monocyte adhesion to human TNFα-activated endothelial cells; benefic effects of amlodipine.

Aims: The objectives of the present study were to investigate the mechanisms of Ninj-1 regulation in TNFα-activated human endothelial cells (HEC), and to test if Amlodipine (AML) ameliorates the inflammatory stress by decreasing Ninj-1 expression.

Main Methods: TNFα-activated HEC with/without AML (0.1 μM and 1 μM) were used.

Lipid Profile Changes Induced by Chronic Administration of Anabolic Androgenic Steroids and Taurine in Rats.

: Anabolic androgenic steroids (AAS), used as a therapy in various diseases and abused in sports, are atherogenic in supraphysiological administration, altering the plasma lipid profile. Taurine, a conditionally-essential amino acid often used in dietary supplements, was acknowledged to delay the onset and progression of atherogenesis, and to mitigate hyperlipidemia. The aim of the present study was to verify if taurine could prevent the alterations induced by concomitant chronic administration of high doses of AAS nandrolone decanoate (DECA) in rats.

Hyperlipidemia Determines Dysfunctional HDL Production and Impedes Cholesterol Efflux in the Small Intestine: Alleviation by Ginger Extract.

Scope: To assess the impact of ginger extract (GIN) in stimulating the production of quality HDL and the cholesterol efflux in the small intestine (SI), key processes in the management of hyperlipidemia (HL)-induced hepatic steatosis, and atherosclerosis.

Methods And Results: Three groups of hamsters are used: (i) N, fed standard diet, (ii) HL, fed high-fat diet for 21 weeks, and (iii) HL-GIN, HL treated with GIN for the last 5 weeks of diet. Apolipoprotein A-I (apoA-I), malondialdehyde-apoA-I (MDA-apoA-I), paraoxonase1 (PON1), and myeloperoxidase (MPO) are measured in plasma and SI.

Zingiber officinale extract administration diminishes steroyl-CoA desaturase gene expression and activity in hyperlipidemic hamster liver by reducing the oxidative and endoplasmic reticulum stress.

Background: Stearoyl CoA desaturases (SCD) are enzymes that convert saturated to monounsaturated fatty acids and have increased activity in hepatic steatosis.

Purpose: We aimed to investigate the potential of ginger extract (GIN) to modulate the liver SCD1 expression and activity in hyperlipidemic (HL) conditions, in order to lower lipid accumulation in the steatotic liver.

Study Design/methods: Male Golden Syrian hamsters were divided in three groups: (i) fed with standard chow (N), (ii) fed with standard chow plus 3% cholesterol and 15% butter for 21 weeks (HL), (iii) HL treated with GIN (800 µg/kg body weight/day) in the last 5 weeks of fat diet (HL-GIN).

Inhibition of miR-486 and miR-92a decreases liver and plasma cholesterol levels by modulating lipid-related genes in hyperlipidemic hamsters.

In the present study we aimed to evaluate the potential of in vivo inhibition of miR-486 and miR-92a to reverse hyperlipidemia, then to identify and validate their lipid metabolism-related target genes. Male Golden-Syrian hamsters fed a hyperlipidemic (HL) diet (standard chow plus 3% cholesterol and 15% butter, 10 weeks) were injected subcutaneously with lock-nucleic acid inhibitors for either miR-486 or miR-92a. Lipids and miRNAs levels in liver and plasma, and hepatic expression of miRNAs target genes were assessed in all HL hamsters.

Dysfunctional high-density lipoproteins have distinct composition, diminished anti-inflammatory potential and discriminate acute coronary syndrome from stable coronary artery disease patients.

There is a stringent need to find means for risk stratification of coronary artery diseases (CAD) patients. We aimed at identifying alterations of plasma high-density lipoproteins (HDL) components and their validation as dysfunctional HDL that could discriminate between acute coronary syndrome (ACS) and stable angina (SA) patients. HDL and HDL were isolated from CAD patients' plasma and healthy subjects.

Caffeic acid attenuates the inflammatory stress induced by glycated LDL in human endothelial cells by mechanisms involving inhibition of AGE-receptor, oxidative, and endoplasmic reticulum stress.

Type 2 diabetes mellitus is a worldwide epidemic and its atherosclerotic complications determine the high morbidity and mortality of diabetic patients. Caffeic acid (CAF), a phenolic acid present in normal diets, is known for its antioxidant properties. The aim of this study was to investigate CAF's anti-inflammatory properties and its mechanism of action, using cultured human endothelial cells (HEC) incubated with glycated low-density lipoproteins (gLDL).

Hyperglycemia Determines Increased Specific MicroRNAs Levels in Sera and HDL of Acute Coronary Syndrome Patients and Stimulates MicroRNAs Production in Human Macrophages.

We aimed to determine the levels of microRNAs (miRNAs) in sera and HDL of acute coronary syndrome (ACS) compared to stable angina (SA) patients with/without hyperglycemia, and evaluate comparatively the functional effect of these sera on the processing machinery proteins (Drosha, DGCR8, Dicer) and miRNAs production in human macrophages. MiRNAs levels in sera and HDL from 35 SA and 72 ACS patients and 30 healthy subjects were measured by using microRNA TaqMan assays. MiR-223, miR-92a, miR-486, miR-122, miR-125a and miR-146a levels were higher in the hyperglycemic ACS compared to normoglycemic sera.

Oxidized LDL-Exposed Human Macrophages Display Increased MMP-9 Expression and Secretion Mediated by Endoplasmic Reticulum Stress.

Oxidatively modified low-density lipoproteins (oxLDL) alter the proper function of the endoplasmic reticulum (ER), inducing ER stress (ERS), which consequently activates inflammatory pathways in macrophages. Matrix metalloproteinase-9 (MMP-9) is the main protease acting on the degradation of the extracellular matrix and the ensuing destabilization of the atherosclerotic plaque. We aimed to investigate whether ERS induced by oxLDL or tunicamycin (TM) in human macrophages is associated with the stimulation of MMP-9 expression and secretion.

Glycated LDL increase VCAM-1 expression and secretion in endothelial cells and promote monocyte adhesion through mechanisms involving endoplasmic reticulum stress.

Type 2 Diabetes Mellitus is a worldwide epidemic, and its atherosclerotic complications produce morbidity and mortality in affected patients. It is known that the vascular cell adhesion molecule-1 (VCAM-1) levels are increased in the sera of diabetic patients. Our aim was to investigate the impact of the endoplasmic reticulum stress (ERS) in VCAM-1 expression and secretion in human endothelial cells (HEC) exposed to glycated low-density lipoproteins (gLDL).