Rationale: MicroRNAs (miRNAs) have been implicated in the epigenetic regulation of key metabolic, inflammatory, and antiangiogenic pathways in type 2 diabetes (DM) and may contribute to common disease complications.Objective: In this study, we explore plasma miRNA profiles in patients with DM. Methods and Results:

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This study applied mass spectrometry-based lipidomics profiling to population-based cohorts and identified molecular lipid signatures for cardiovascular disease. Molecular lipid species constitute promising new biomarkers that outperform the conventional biochemical measurements of lipid classes currently used in clinics.

Free fatty acids are considered to be the major energy source for the myocardium. To investigate the metabolic fate of this substrate in humans, 24 subjects underwent coronary sinus and arterial catheterization. 13 subjects were healthy volunteers and 11 subjects had symptoms of ischemic heart disease. I1-14CIoleate or 11-'4Cipalmitate bound to albumin was infused at a constant rate of 25 1Ci/h. Oxidation was determined by measuring the '4C02 production. The data demonstrated that a high percentage (84±17%) of the palmitate and oleate extracted by the myocardium underwent rapid oxidation. A highly significant correlation was present between the arterial level and the amount oxidized (r = 0.82, P < 0.001 for palmitate; r = 0.77, P < 0.001 for oleate). The isotope extraction ratio was greater than the chemical extraction ratio. This difference of 6±2 nmol/ml of blood in the young normal subjects was significantly less than the 12±4 nmol/ml observed in the ischemic heart disease patients (P < 0.001).

IntroductionNumerous studies have demonstrated that endothelial progenitor cells (EPCs) are present among peripheral blood mononuclear cells (PBMNCs) and represent a subset of circulating bone marrow mononuclear cells (BMCs), which have the capacity to differentiate into endothelial cells in vivo. 1 New concepts of stem cell-based therapies for myocardial regeneration resulted in a rapid translation into a clinical context. [2][3][4] Yet, key questions remain unanswered. Importantly, the nomenclature and the phenotype of EPCs are subject to ongoing controversy and there are currently no specific markers that unambiguously identify these cells. 5,6 Thus, a more comprehensive approach is needed to analyze their antigenic profiles.MPs are small membrane vesicles (0.2-1.0 m) that originate from the plasma membrane and are shed from the cell surface after activation and apoptosis. 7 Importantly, MPs retain membrane antigens specific for the parent cell they originate from. Thus, MPs represent an ideal subproteome to clarify the cellular progeny of EPC cultures and mass spectrometry is the instrument of choice for this kind of research. 8 In this study, we used a proteomic approach to identify membrane proteins present on MPs in EPC cultures. Methods EPC cultureThe study was approved by the ethics review board of J. W. Goethe University and King's College London. Peripheral blood was collected from healthy adult volunteers and informed consent was obtained in accordance with the Declaration of Helsinki. EPC cultures were performed as previously described. 9,10 In brief, PBMNCs from healthy volunteers were isolated by Lymphoprep (1.077 g/mL; Axis-Shield PoCAS) density barrier centrifugation. The low-density fraction (Ͻ 1.077 g/mL) was carefully removed from the interface and washed 3 times with PBS (Dulbecco phosphate-buffered saline; Sigma-Aldrich) containing 2% FBS (fetal bovine serum, filtered and heat inactivated; Gibco, Invitrogen). Immediately after isolation, the cells were counted and 8 ϫ 10 6 cells were plated on fibronectin-coated (10 g/mL fibronectin from human plasma; SigmaAldrich) 12-well plates containing 1 mL endothelial basal medium (EBM; Cambrex Bio Science) supplemented with 20% FBS, EGM SingleQuots (10 g/mL epidermal growth factor, 3 g/mL bovine brain extract, 50 g/mL gentamicine, 50 g/mL amphotericin-B, 1 g/mL hydrocortisone; Cambrex Bio Science) and 10 ng/mL human vascular endothelial growth factor 165 (hVEGF 165; R&D Systems). Before use, the medium was passed through a 0.2-m filter. After 3 days in culture, the nonadherent An Inside Blood analysis of this article appears at the front of this issue.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 11, 2018. by guest www.bloodjournal.org From cells were removed and fresh EBM medium was added. T...

Background: The adult mammalian heart has limited regenerative capacity, mostly attributable to postnatal cardiomyocyte cell cycle arrest. In the last 2 decades, numerous studies have explored cardiomyocyte cell cycle regulatory mechanisms to enhance myocardial regeneration after myocardial infarction. Pkm2 (Pyruvate kinase muscle isoenzyme 2) is an isoenzyme of the glycolytic enzyme pyruvate kinase. The role of Pkm2 in cardiomyocyte proliferation, heart development, and cardiac regeneration is unknown. Methods: We investigated the effect of Pkm2 in cardiomyocytes through models of loss (cardiomyocyte-specific Pkm2 deletion during cardiac development) or gain using cardiomyocyte-specific Pkm2 modified mRNA to evaluate Pkm2 function and regenerative affects after acute or chronic myocardial infarction in mice. Results: Here, we identify Pkm2 as an important regulator of the cardiomyocyte cell cycle. We show that Pkm2 is expressed in cardiomyocytes during development and immediately after birth but not during adulthood. Loss of function studies show that cardiomyocyte-specific Pkm2 deletion during cardiac development resulted in significantly reduced cardiomyocyte cell cycle, cardiomyocyte numbers, and myocardial size. In addition, using cardiomyocyte-specific Pkm2 modified RNA, our novel cardiomyocyte-targeted strategy, after acute or chronic myocardial infarction, resulted in increased cardiomyocyte cell division, enhanced cardiac function, and improved long-term survival. We mechanistically show that Pkm2 regulates the cardiomyocyte cell cycle and reduces oxidative stress damage through anabolic pathways and β-catenin. Conclusions: We demonstrate that Pkm2 is an important intrinsic regulator of the cardiomyocyte cell cycle and oxidative stress, and highlight its therapeutic potential using cardiomyocyte-specific Pkm2 modified RNA as a gene delivery platform.

OSE biomarkers predict 15-year CVD and stroke outcomes and provide potential clinical utility by reclassifying a significant proportion of individuals into higher or lower risk categories after traditional risk assessment.

The present study characterized the metabolic adaptation to persistent AF, unraveling a potential role for ketone bodies, and demonstrated that discordant metabolic alterations are evident in individuals susceptible to post-operative AF.