RNAase III-Type Enzyme Dicer Regulates Mitochondrial Fatty Acid Oxidative Metabolism in Cardiac Mesenchymal Stem Cells

Cardiac mesenchymal stem cells (C-MSC) play a key role in maintaining normal cardiac function under physiological and pathological conditions. Glycolysis and mitochondrial oxidative phosphorylation predominately account for energy production in C-MSC. Dicer, a ribonuclease III endoribonuclease, plays a critical role in the control of microRNA maturation in C-MSC, but its role in regulating C-MSC energy metabolism is largely unknown. In this study, we found that Dicer knockout led to concurrent increase in both cell proliferation and apoptosis in C-MSC compared to Dicer floxed C-MSC. We analyzed mitochondrial oxidative phosphorylation by quantifying cellular oxygen consumption rate (OCR), and glycolysis by quantifying the extracellular acidification rate (ECAR), in C-MSC with/without Dicer gene deletion. Dicer gene deletion significantly reduced mitochondrial oxidative phosphorylation while increasing glycolysis in C-MSC. Additionally, Dicer gene deletion selectively reduced the expression of β-oxidation genes without affecting the expression of genes involved in the tricarboxylic acid (TCA) cycle or electron transport chain (ETC). Finally, Dicer gene deletion reduced the copy number of mitochondrially encoded 1,4-Dihydronicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase core subunit 6 (MT-ND6), a mitochondrial-encoded gene, in C-MSC. In conclusion, Dicer gene deletion induced a metabolic shift from oxidative metabolism to aerobic glycolysis in C-MSC, suggesting that Dicer functions as a metabolic switch in C-MSC, which in turn may regulate proliferation and environmental adaptation

Role of arginase 2 in systemic metabolic activity and adipose tissue fatty acid metabolism in diet-induced obese mice

Visceral adipose tissue (VAT) inflammation and metabolic dysregulation are key components of obesity-induced metabolic disease. Upregulated arginase, a ureahydrolase enzyme with two isoforms (A1-cytosolic and A2-mitochondrial), is implicated in pathologies associated with obesity and diabetes. This study examined A2 involvement in obesity-associated metabolic and vascular disorders. WT and globally deleted A2(−/−) or A1(+/−) mice were fed either a high fat/high sucrose (HFHS) diet or normal diet (ND) for 16 weeks. Increases in body and VAT weight of HFHS-fed WT mice were abrogated in A2−/−, but not A1+/−, mice. Additionally, A2−/− HFHS-fed mice exhibited higher energy expenditure, lower blood glucose, and insulin levels compared to WT HFHS mice. VAT and adipocytes from WT HFHS fed mice showed greater A2 expression and adipocyte size and reduced expression of PGC-1α, PPAR-γ, and adiponectin. A2 deletion blunted these effects, increased levels of active AMPK-α, and upregulated genes involved in fatty acid metabolism. A2 deletion prevented HFHS-induced VAT collagen deposition and inflammation, which are involved in adipocyte metabolic dysfunction. Endothelium-dependent vasorelaxation, impaired by HFHS diet, was significantly preserved in A2−/− mice, but more prominently maintained in A1+/− mice. In summary, A2 is critically involved in HFHS-induced VAT inflammation and metabolic dysfunction

Deficiency in Nrf2 transcription factor decreases adipose tissue mass and hepatic lipid accumulation in leptin‐deficient mice

Objective: To evaluate whether Nrf2 deficiency impacts insulin resistance and lipid accumulation in liver and white adipose tissue. Methods: Lepob/ob mice (OB) with targeted Nrf2 deletion (OB‐Nrf2KO) were generated. Pathogenesis of obesity and type 2 diabetes was measured in C57BL/6J, Nrf2KO, OB, and OB‐Nrf2KO mice. Hepatic lipid content, lipid clearance, and very low‐density lipoprotein (VLDL) secretion were determined between OB and OB‐Nrf2KO mice. Results: OB‐Nrf2KO mice exhibited decreased white adipose tissue mass and decreased adipogenic and lipogenic gene expression compared with OB mice. Nrf2 deficiency prolonged hyperglycemia in response to glucose challenge, which was paralleled by reduced insulin‐stimulated Akt phosphorylation. In OB mice, Nrf2 deficiency decreased hepatic lipid accumulation, decreased peroxisome proliferator‐activated receptor γ expression and nicotinamide adenine dinucleotide phosphate (NADPH) content, and enhanced VLDL secretion. However, this observation was opposite in lean mice. Additionally, OB‐Nrf2KO mice exhibited increased plasma triglyceride content, decreased HDL‐cholesterol content, and enhanced apolipoprotein B expression, suggesting Nrf2 deficiency caused dyslipidemia in these mice. Conclusions: Nrf2 deficiency in Lepob/ob mice reduced white adipose tissue mass and prevented hepatic lipid accumulation but induced insulin resistance and dyslipidemia. This study indicates a dual role of Nrf2 during metabolic dysregulation—increasing lipid accumulation in liver and white adipose tissue but preventing lipid accumulation in obese mice

The lifelong impact of fetal growth restriction on cardiac development

Background: Maternal nutrient restriction (MNR) is a widespread cause of fetal growth restriction (FGR), an independent predictor of heart disease and cardiovascular mortality. Our objective was to examine the developmental and long-term impact of MNR-induced FGR on cardiac structure in a model that closely mimics human development. Methods: A reduction in total caloric intake spanning pregestation through to lactation in guinea pig sows was used to induce FGR. Proliferation, differentiation, and apoptosis of cardiomyocytes were assessed in late-gestation fetal, neonatal, and adult guinea pig hearts. Proteomic analysis and pathway enrichment were performed on fetal hearts. Results: Cardiomyocyte proliferation and the number of mononucleated cells were enhanced in the MNR–FGR fetal and neonatal heart, suggesting a delay in cardiomyocyte differentiation. In fetal hearts of MNR–FGR animals, apoptosis was markedly elevated and the total number of cardiomyocytes reduced, the latter remaining so throughout neonatal and into adult life. A reduction in total cardiomyocyte number in adult MNR–FGR hearts was accompanied by exaggerated hypertrophy and a disorganized architecture. Pathway analysis identified genes related to cell proliferation, differentiation, and survival. Conclusions: FGR influences cardiomyocyte development during critical windows of development, leading to a permanent deficiency in cardiomyocyte number and compensatory hypertrophy in a rodent model that recapitulates human development

Neurofibromin Deficiency Induces Endothelial Cell Proliferation and Retinal Neovascularization

Purpose: Neurofibromatosis type 1 (NF1) is the result of inherited mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. Eye manifestations are common in NF1 with recent reports describing a vascular dysplasia in the retina and choroid. Common features of NF1 retinopathy include tortuous and dilated feeder vessels that terminate in capillary tufts, increased endothelial permeability, and neovascularization. Given the retinal vascular phenotype observed in persons with NF1, we hypothesize that preserving neurofibromin may be a novel strategy to control pathologic retinal neovascularization. Methods: Nf1 expression in human endothelial cells (EC) was reduced using small hairpin (sh) RNA and EC proliferation, migration, and capacity to form vessel-like networks were assessed in response to VEGF and hypoxia. Wild-type (WT), Nf1 heterozygous (Nf1+/-), and Nf1flox/+;Tie2cre pups were subjected to hyperoxia/hypoxia using the oxygen-induced retinopathy model. Retinas were analyzed quantitatively for extent of retinal vessel dropout, neovascularization, and capillary branching. Results: Neurofibromin expression was suppressed in response to VEGF, which corresponded with activation of Mek-Erk and PI3-K-Akt signaling. Neurofibromin-deficient EC exhibited enhanced proliferation and network formation in response to VEGF and hypoxia via an Akt-dependent mechanism. In response to hyperoxia/hypoxia, Nf1+/- retinas exhibited increased vessel dropout and neovascularization when compared with WT retinas. Neovascularization was similar between Nf1+/- and Nf1flox/+;Tie2cre retinas, but capillary drop out in Nf1flox/+;Tie2cre retinas was significantly reduced when compared with Nf1+/- retinas. Conclusions: These data suggest that neurofibromin expression is essential for controlling endothelial cell proliferation and retinal neovascularization and therapies targeting neurofibromin-deficient EC may be beneficial

Endothelin‐1 response to whole‐body vibration in obese and normal weight individuals

Upregulation of endothelin‐1 (ET‐1) is the hallmark of various cardiovascular diseases (CVD). The purpose of the present study was to assess the ET‐1 response to an acute bout of whole‐body vibration (WBV) in humans and to determine the role of adiposity. Twenty‐two participants volunteered for the study; they were grouped into overweight/obese [(OW/OB): n = 11, Age: 33 ± 4 years, Body mass index (BMI): 35 ± 10 kg/m(2)] or normal weight [(NW): n = 11, Age: 28 ± 7 years, BMI: 21 ± 2 kg/m(2)]. Participants engaged in 10 cycles of WBV exercise (1 cycle = 1 min WBV followed by 30 s of rest). Blood samples were analyzed for ET‐1 pre‐WBV (PRE), immediately post (POST), 1 h (1H), 3 h (3H), and 24 h (24H) post‐WBV. There was a significant time main effect of WBV on circulating ET‐1 (F = 12.5, p < 0.001); however, the ET‐1 response was similar (F = 0.180, p = 0.677) between groups. Specifically, compared to PRE, a significant increase in ET‐1 was observed at 1H (p = 0.017) and 3H (p = 0.025). In addition, concentrations of ET‐1 were significantly lower at 24H compared to PRE (p = 0.019), 1H (p < 0.001), and 3H (p < 0.001). Maximal oxygen uptake during WBV was similar between the two groups. Acute WBV resulted in an initial rise in ET‐1, followed by a significantly lower ET‐1 at 24H in both groups. Findings support the utility of routine WBV exercise to elicit a decrease in ET‐1 and improve CVD risk, similar to what has been reported with traditional modes of exercise

Spontaneous left main coronary artery dissection complicated by pseudoaneurysm formation in pregnancy: role of CT coronary angiography

We report a case of a 26-year-old female, who presented at 34 weeks of an uncomplicated pregnancy with an acute ST elevation anterior wall myocardial infarction. Cardiac catheterization suggested a left main coronary artery dissection with pseudoaneurysm formation. The patient's course was complicated by congestive heart failure. She was initially managed conservatively by a multidisciplinary team including heart failure specialists, obstetricians, and cardiovascular surgeons. 4 days after admission, her LMC was imaged by dual-source 64 slice Cardiac computed tomography, coronary dissection was identified extending to the lumen, and the presence of pseudoaneurysm was confirmed. She underwent subsequently a staged procedure, which included placement of an intra-aortic balloon pump, cesarean section, and coronary artery bypass grafting. This case illustrates the utility of coronary artery CT imaging to assess the complexity and stability of coronary artery dissections, thereby helping to determine the need for, and timing of revascularization procedures

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation