Micro-RNA 7975 directly regulates MDTH expression and mediates endothelial cell proliferation and migration in the development of early atherosclerosis.

Cardiovascular disease (CVD) is commonly due to the development of atherosclerosis. Endothelial integrity is critical in the prevention of pathogenesis of atherosclerosis. The key to prevention of CVD is understanding the molecular mechanisms responsible for initiation of early atherosclerosis.

Sex, Racial, and Ethnic Disparities in Acute Coronary Syndrome: Novel Risk Factors and Recommendations for Earlier Diagnosis to Improve Outcomes.

In this review, sex, racial, and ethnic differences in acute coronary syndromes on a global scale are summarized. The relationship between disparities in presentation and management of acute coronary syndromes and effect on worse clinical outcomes in acute coronary syndromes are discussed. The effect of demographic, geographic, racial, and ethnic factors on acute coronary syndrome care disparities are reviewed.

Potential miRNA biomarkers and therapeutic targets for early atherosclerotic lesions.

Identification of potential therapeutic targets and biomarkers indicative of burden of early atherosclerosis that occur prior to advancement to life-threatening unstable plaques is the key to eradication of CAD prevalence and incidences. We challenged 16 baboons with a high cholesterol, high fat diet for 2 years and evaluated early-stage atherosclerotic lesions (fatty streaks, FS, and fibrous plaques, FP) in formalin-fixed common iliac arteries (CIA). We used small RNA sequencing to identify expressed miRNAs in CIA and in baseline blood samples of the same animals.

Breath biomarkers of insulin resistance in pre-diabetic Hispanic adolescents with obesity.

Insulin resistance (IR) affects a quarter of the world's adult population and is a major factor in the pathogenesis of cardio-metabolic disease. In this pilot study, we implemented a non-invasive breathomics approach, combined with random forest machine learning, to investigate metabolic markers from obese pre-diabetic Hispanic adolescents as indicators of abnormal metabolic regulation. Using the ReCIVA breathalyzer device for breath collection, we have identified a signature of 10 breath metabolites (breath-IR model), which correlates with Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) (R = 0.

Integrated omics analysis reveals sirtuin signaling is central to hepatic response to a high fructose diet.

Background: Dietary high fructose (HFr) is a known metabolic disruptor contributing to development of obesity and diabetes in Western societies. Initial molecular changes from exposure to HFr on liver metabolism may be essential to understand the perturbations leading to insulin resistance and abnormalities in lipid and carbohydrate metabolism. We studied vervet monkeys (Clorocebus aethiops sabaeus) fed a HFr (n=5) or chow diet (n=5) for 6 weeks, and obtained clinical measures of liver function, blood insulin, cholesterol and triglycerides.

Sex Differences in MicroRNA Expression and Cardiometabolic Risk Factors in Hispanic Adolescents with Obesity.

Objective: To evaluate sex differences in microRNA (miRNA) expression, anthropometric measures, and cardiometabolic risk factors in Hispanic adolescents with obesity.

Study Design: Cross-sectional study of 68 (60% male) Hispanic adolescents with obesity, aged 13-17 years, recruited from a pediatric weight management clinic. We used small RNA sequencing to identify differentially expressed circulating miRNAs.

Diet-induced leukocyte telomere shortening in a baboon model for early stage atherosclerosis.

Reported associations between leukocyte telomere length (LTL) attrition, diet and cardiovascular disease (CVD) are inconsistent. This study explores effects of prolonged exposure to a high cholesterol high fat (HCHF) diet on LTL in a baboon model of atherosclerosis. We measured LTL by qPCR in pedigreed baboons fed a chow (n = 105) or HCHF (n = 106) diet for 2 years, tested for effects of diet on LTL, and association between CVD risk factors and atherosclerotic lesions with LTL.

Histological variation of early stage atherosclerotic lesions in baboons after prolonged challenge with high-cholesterol, high-fat diet.

Introduction: The baboon is a well-characterized model of human early stage atherosclerosis. However, histological and morphological changes involved in atherogenesis in baboons are not known. Previously, we challenged baboons with a high-cholesterol, high-fat diet for two years and observed fatty streak and plaque lesions in iliac arteries (RCIA).

Identification of coordinately regulated microRNA-gene networks that differ in baboons discordant for LDL-cholesterol.

Rationale: Plasma low-density lipoprotein cholesterol (plasma LDL-C), vascular endothelial cells and peripheral blood mononuclear cells (PBMCs), particularly monocytes, play key roles in initiating atherosclerosis, the primary cause of cardiovascular disease (CVD). Although the mechanisms underlying development of atherosclerosis are not well understood, LDL-C is known to influence expression of endothelial microRNAs (miRNAs) and gene-targets of miRNAs to promote cell senescence. However, the impact of LDL-C on expression of PBMC miRNAs and miRNA targeted genes in response to an atherogenic diet is not known.

Nonhuman Primates and Translational Research-Cardiovascular Disease.

Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in the United States. Human epidemiological studies provide challenges for understanding mechanisms that regulate initiation and progression of CVD due to variation in lifestyle, diet, and other environmental factors. Studies describing metabolic and physiologic aspects of CVD, and those investigating genetic and epigenetic mechanisms influencing CVD initiation and progression, have been conducted in multiple Old World nonhuman primate (NHP) species.

Diet-induced early-stage atherosclerosis in baboons: Lipoproteins, atherogenesis, and arterial compliance.

Background: The purpose of this study was to determine whether dietary manipulation can reliably induce early-stage atherosclerosis and clinically relevant changes in vascular function in an established, well-characterized non-human primate model.

Methods: We fed 112 baboons a high-cholesterol, high-fat challenge diet for two years. We assayed circulating biomarkers of cardiovascular disease (CVD) risk, at 0, 7, and 104 weeks into the challenge; assessed arterial compliance noninvasively at 104 weeks; and measured atherosclerotic lesions in three major arteries at necropsy.

Baboons as a model to study genetics and epigenetics of human disease.

A major challenge for understanding susceptibility to common human diseases is determining genetic and environmental factors that influence mechanisms underlying variation in disease-related traits. The most common diseases afflicting the US population are complex diseases that develop as a result of defects in multiple genetically controlled systems in response to environmental challenges. Unraveling the etiology of these diseases is exceedingly difficult because of the many genetic and environmental factors involved.

Identification of candidate genes encoding an LDL-C QTL in baboons.

Cardiovascular disease (CVD) is the leading cause of death in developed countries, and dyslipidemia is a major risk factor for CVD. We previously identified a cluster of quantitative trait loci (QTL) on baboon chromosome 11 for multiple, related quantitative traits for serum LDL-cholesterol (LDL-C). Here we report differentially regulated hepatic genes encoding an LDL-C QTL that influences LDL-C levels in baboons.

Enhancing genotyping of MAOA-LPR and 5-HTT-LPR in rhesus macaques (Macaca mulatta).

Background: Genetic variation in monoamine oxidase A (MAOA) and serotonin transporter (5-HTT)-linked polymorphic regions (LPR) is associated with neuropsychiatric behavior.

Methods: We genotyped 37 macaques using conventional PCR product gel fractionation and by capillary electrophoresis of multiplexed amplicons and compared the data.

Results: Genotype concordance was 97% and 95% for MAOA-LPR and 5-HTT-LPR, respectively.

Differential microRNA response to a high-cholesterol, high-fat diet in livers of low and high LDL-C baboons.

Background: Dysregulation of microRNA (miRNA) expression has been implicated in molecular genetic events leading to the progression and development of atherosclerosis. We hypothesized that miRNA expression profiles differ between baboons with low and high serum low-density lipoprotein cholesterol (LDL-C) concentrations in response to diet, and that a subset of these miRNAs regulate genes relevant to dyslipidemia and risk of atherosclerosis.

Results: Using Next Generation Illumina sequencing methods, we sequenced hepatic small RNA libraries from baboons differing in their LDL-C response to a high-cholesterol, high-fat (HCHF) challenge diet (low LDL-C, n = 3; high LDL-C, n = 3), resulting in 517 baboon miRNAs: 490 were identical to human miRNAs and 27 were novel.

Identification of baboon microRNAs expressed in liver and lymphocytes.

Background: MicroRNAs (miRNAs) are small noncoding RNAs (~22 nucleotides) that regulate gene expression by cleaving mRNAs or inhibiting translation. The baboon is a well-characterized cardiovascular disease model; however, no baboon miRNAs have been identified. Evidence indicates that the baboon and human genomes are highly conserved; based on this conservation, we hypothesized that comparative genomic methods could be used to identify baboon miRNAs.

Enhancing radiation hybrid mapping through whole genome amplification.

Radiation hybrid (RH) mapping is limited by the inherent genomic instability of RH clones entailing both, limited DNA sample amounts and genomic heterogeneity of the clones. Here the instability of RH clones is quantified and the suitability of the multiple strand displacement whole genome amplification method (WGA) for radiation hybrid mapping is assessed. To quantify the instability of RH clones, eleven clones of a 10,000(Rad) rhesus macaque radiation hybrid panel were passaged ten times and analyzed by interspersed repeat sequence specific quantitative PCR and by genotyping of 46 macaque chromosome 5 STS markers.

Serotonin pathway gene-gene and gene-environment interactions influence behavioral stress response in infant rhesus macaques.

A subset of serotonin (5-HT) pathway polymorphisms has been shown to confer risk for psychological dysfunction, particularly in individuals who experience early adversity. Understanding the developmental processes underlying these Gene x Environment interactions will strengthen the search for risk factors for behavioral dysfunction. We investigated the combined influence of two serotonin pathway polymorphisms and species-atypical, and possibly adverse, rearing (nursery rearing [NR]) on two dimensions of behavioral stress response in infant rhesus macaques.

What is an "adverse" environment? Interactions of rearing experiences and MAOA genotype in rhesus monkeys.

Background: Studies have been inconsistent in demonstrating that early adversity and specific genotype can be joint risk factors for poor behavioral outcomes. Using a rhesus monkey model, we examined how social context and different forms of early adversity influence whether a specific genotype (polymorphism in the promoter region of monoamine oxidase A [MAOA]) affects display of aggressive, fearful, and anxious behaviors.

Methods: Rhesus monkey infants (n = 473) were exposed to brief social challenge at age 3-4 months.

A high-resolution radiation hybrid map of rhesus macaque chromosome 5 identifies rearrangements in the genome assembly.

A 10,000-rad radiation hybrid (RH) cell panel of the rhesus macaque was generated to construct a comprehensive RH map of chromosome 5. The map represents 218 markers typed in 185 RH clones. The 4846-cR map has an average marker spacing of 798 kb.