Project description:Extracellular vesicles (EV) are cell-secreted, nano-sized membrane particles with various molecular cargo, including metabolites, proteins and nucleic acids [1] . EVs are involved in various physiological and pathological functions, including that of the myocardium [2] , such as cardiac stress adaptation mechanisms [3] . Metabolic co-morbidities can ameliorate the innate stress response of the heart [4], [5] . Furthermore, one of the most common metabolic co-morbidities, type-II diabetes, can inhibit EV- mediated cardioprotection [6] . EVs of high-fat fed animals can also exacerbate ischemic cardiac damage and induce cell death of cardiomyocytes (CM) [7], [8] . Therefore, metabolic diseases might interfere with the effect of cardiac EVs by various mechanisms. However, as of now, little is known about the effect of hypercholesterolemia (HC) on cardiovascular EV communication. Analyzing EVs of the circulation might lead to novel diagnostic tools and to better understanding of disease conditions. As of now it is evidenced that circulating EV number is increased in metabolic diseases [9]–[11] , including familiar hypercholesterolemia [12], [13] , in which their amount is associated with the risk of cardiovascular diseases [14], [15] as well. However, to understand the biological role of EV-related changes in cardiometabolic diseases, characterization of EV composition is needed. The main molecular constituents of EVs are membrane lipids and other metabolites, intravesicular and transmembrane proteins and nucleotides. Change in any of these constituents may result in an altered biological response. Barrachina et. al. has analyzed the dysregulated protein composition of circulating EVs in obesity [16] and in a similar study, miRNA cargo of EVs from obese patients was analyzed, as well [17] , however, it has not been assessed if HC alters EV metabolome, thus, function. EVs contribute to response to various stresses in the myocardium [18] , but as of now, we do not know HC influences EV release of CMs. One of the major effects of HC is cardiac- and systemic inflammation [19] . Earlier studies showed in various disease conditions, such as angiotensin II-induced hypertrophy, that CM EVs activate monocytes, thereby contribute to inflammation [20], [21] . In contrast, in hypoxic conditions, EVs promote macrophage polarization to the reparative M2 phenotype [22], [23] . Thus, we hypothesized that CM EVs might play a role in HC-induced cardiac inflammation. In this study, we aimed to analyze how HC affects the metabolic composition of EVs and how HC modifies CM EV communication. Therefore, we have analyzed the metabolome of circulating EVs of HC- fed rats and compared the identified changes to the plasma metabolome. In addition, for the first time, we assessed how HC affects the biophysical and biochemical properties of CM EVs and we analyzed their role in immune activation.

Project description:AimsTo investigate whether metabolic signature composed of multiple plasma metabolites can be used to characterize adherence and metabolic response to the Mediterranean diet and whether such a metabolic signature is associated with cardiovascular disease (CVD) risk.Methods and resultsOur primary study cohort included 1859 participants from the Spanish PREDIMED trial, and validation cohorts included 6868 participants from the US Nurses' Health Studies I and II, and Health Professionals Follow-up Study (NHS/HPFS). Adherence to the Mediterranean diet was assessed using a validated Mediterranean Diet Adherence Screener (MEDAS), and plasma metabolome was profiled by liquid chromatography-tandem mass spectrometry. We observed substantial metabolomic variation with respect to Mediterranean diet adherence, with nearly one-third of the assayed metabolites significantly associated with MEDAS (false discovery rate < 0.05). Using elastic net regularized regressions, we identified a metabolic signature, comprised of 67 metabolites, robustly correlated with Mediterranean diet adherence in both PREDIMED and NHS/HPFS (r = 0.28-0.37 between the signature and MEDAS; P = 3 × 10-35 to 4 × 10-118). In multivariable Cox regressions, the metabolic signature showed a significant inverse association with CVD incidence after adjusting for known risk factors (PREDIMED: hazard ratio [HR] per standard deviation increment in the signature = 0.71, P < 0.001; NHS/HPFS: HR = 0.85, P = 0.001), and the association persisted after further adjustment for MEDAS scores (PREDIMED: HR = 0.73, P = 0.004; NHS/HPFS: HR = 0.85, P = 0.004). Further genome-wide association analysis revealed that the metabolic signature was significantly associated with genetic loci involved in fatty acids and amino acids metabolism. Mendelian randomization analyses showed that the genetically inferred metabolic signature was significantly associated with risk of coronary heart disease (CHD) and stroke (odds ratios per SD increment in the genetically inferred metabolic signature = 0.92 for CHD and 0.91 for stroke; P < 0.001).ConclusionsWe identified a metabolic signature that robustly reflects adherence and metabolic response to a Mediterranean diet, and predicts future CVD risk independent of traditional risk factors, in Spanish and US cohorts.

Project description:Background. HIV-infected individuals on antiretroviral therapy (HIV/ART) experience higher levels of non-AIDS morbidity than uninfected people, which is believed to be driven by inflammation that persists despite viral suppression. Elevations in plasma cytokines, coagulation markers and both innate and adaptive immune cell activation during untreated infection are often incompletely reversed by ART and associated with these morbidities. Monocytes/macrophages play a central role in many of these complications including neurocognitive and cardiovascular disease. Results. We investigated monocyte surface markers, gene expression and plasma cytokines in 11 HIV-infected older individuals (median age 53 years) who started therapy with low CD4 counts (median 129 cells/ul), with elevated hsCRP (≥2mg/L) despite long-term ART (median 7.4 years), along with age, gender, race and smoking status-matched controls. Major monocyte subsets (based on CD14/CD16/CD163) were not different from controls, but surface levels differed for CD163 (p=0.022), PD1 (p=0.015) and a trend for tissue factor (p=0.098). As a group, HIV/ART subjects had elevated levels of plasma CCL2 (MCP-1; p=0.0001), CXCL9 (MIG; p=0.04) and sIL2R (p=0.015), which were highly correlated, whereas sCD14 and several other markers were not significantly elevated. However, principal component analysis of soluble markers revealed that about half of HIV/ART subjects clustered with controls, whereas the remainder were distinct, driven by IL-10, CCL11, CXCL10, CXCL11 as well as CCL2, CXCL9 and sIL2R. Outlier subjects were significantly older than those who clustered with controls. Gene expression analysis unexpectedly revealed downregulation in HIV/ART monocytes of multiple genes linked to immune functions including inflammation, immune cell development and cell-cell signaling. Conclusions. These results reveal a novel pattern of immune dysregulation involving both aberrant inflammation and monocyte dysfunction, which suggests complex mechanisms linking monocytes and HIV/ART comorbidities.

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Cardiovascular risk in patients with type 2 diabetes is associated with alteration of blood monocyte phenotype and plasma metabolome

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