IMPORTANCE: The prevalence of diabetes among Hispanic and Asian American subpopulations in the United States is unknown. OBJECTIVE: To estimate racial/ethnic differences in the prevalence of diabetes ...among US adults 20 years or older by major race/ethnicity groups and selected Hispanic and non-Hispanic Asian subpopulations. DESIGN, SETTING, AND PARTICIPANTS: National Health and Nutrition Examination Surveys, 2011-2016, cross-sectional samples representing the noninstitutionalized, civilian, US population. The sample included adults 20 years or older who had self-reported diagnosed diabetes during the interview or measurements of hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and 2-hour plasma glucose (2hPG). EXPOSURES: Race/ethnicity groups: non-Hispanic white, non-Hispanic black, Hispanic and Hispanic subgroups (Mexican, Puerto Rican, Cuban/Dominican, Central American, and South American), non-Hispanic Asian and non-Hispanic Asian subgroups (East, South, and Southeast Asian), and non-Hispanic other. MAIN OUTCOMES AND MEASURES: Diagnosed diabetes was based on self-reported prior diagnosis. Undiagnosed diabetes was defined as HbA1c 6.5% or greater, FPG 126 mg/dL or greater, or 2hPG 200 mg/dL or greater in participants without diagnosed diabetes. Total diabetes was defined as diagnosed or undiagnosed diabetes. RESULTS: The study sample included 7575 US adults (mean age, 47.5 years; 52% women; 2866 65% non-Hispanic white, 1636 11% non-Hispanic black, 1952 15% Hispanic, 909 6% non-Hispanic Asian, and 212 3% non-Hispanic other). A total of 2266 individuals had diagnosed diabetes; 377 had undiagnosed diabetes. Weighted age- and sex-adjusted prevalence of total diabetes was 12.1% (95% CI, 11.0%-13.4%) for non-Hispanic white, 20.4% (95% CI, 18.8%-22.1%) for non-Hispanic black, 22.1% (95% CI, 19.6%-24.7%) for Hispanic, and 19.1% (95% CI, 16.0%-22.1%) for non-Hispanic Asian adults (overall P < .001). Among Hispanic adults, the prevalence of total diabetes was 24.6% (95% CI, 21.6%-27.6%) for Mexican, 21.7% (95% CI, 14.6%-28.8%) for Puerto Rican, 20.5% (95% CI, 13.7%-27.3%) for Cuban/Dominican, 19.3% (95% CI, 12.4%-26.1%) for Central American, and 12.3% (95% CI, 8.5%-16.2%) for South American subgroups (overall P < .001). Among non-Hispanic Asian adults, the prevalence of total diabetes was 14.0% (95% CI, 9.5%-18.4%) for East Asian, 23.3% (95% CI, 15.6%-30.9%) for South Asian, and 22.4% (95% CI, 15.9%-28.9%) for Southeast Asian subgroups (overall P = .02). The prevalence of undiagnosed diabetes was 3.9% (95% CI, 3.0%-4.8%) for non-Hispanic white, 5.2% (95% CI, 3.9%-6.4%) for non-Hispanic black, 7.5% (95% CI, 5.9%-9.1%) for Hispanic, and 7.5% (95% CI, 4.9%-10.0%) for non-Hispanic Asian adults (overall P < .001). CONCLUSIONS AND RELEVANCE: In this nationally representative survey of US adults from 2011 to 2016, the prevalence of diabetes and undiagnosed diabetes varied by race/ethnicity and among subgroups identified within the Hispanic and non-Hispanic Asian populations.
OBJECTIVE—During inflammation, macrophages secrete vesicles carrying RNA, protein, and lipids as a form of extracellular communication. In the vessel wall, extracellular vesicles (EVs) have been ...shown to be transferred between vascular cells during atherosclerosis; however, the role of macrophage-derived EVs in atherogenesis is not known. Here, we hypothesize that atherogenic macrophages secrete microRNAs (miRNAs) in EVs to mediate cell–cell communication and promote proinflammatory and proatherogenic phenotypes in recipient cells.
APPROACH AND RESULTS—We isolated EVs from mouse and human macrophages treated with an atherogenic stimulus (oxidized low-density lipoprotein) and characterized the EV miRNA expression profile. We confirmed the enrichment of miR-146a, miR-128, miR-185, miR-365, and miR-503 in atherogenic EVs compared with controls and demonstrate that these EVs are taken up and transfer exogenous miRNA to naive recipient macrophages. Bioinformatic pathway analysis suggests that atherogenic EV miRNAs are predicted to target genes involved in cell migration and adhesion pathways, and indeed delivery of EVs to naive macrophages reduced macrophage migration both in vitro and in vivo. Inhibition of miR-146a, the most enriched miRNA in atherogenic EVs, reduced the inhibitory effect of EVs on macrophage migratory capacity. EV-mediated delivery of miR-146a repressed the expression of target genes IGF2BP1 (insulin-like growth factor 2 mRNA-binding protein 1) and HuR (human antigen R or ELAV-like RNA-binding protein 1) in recipient cells, and knockdown of IGF2BP1 and HuR using short interfering RNA greatly reduced macrophage migration, highlighting the importance of these EV-miRNA targets in regulating macrophage motility.
CONCLUSIONS—EV-derived miRNAs from atherogenic macrophages, in particular miR-146a, may accelerate the development of atherosclerosis by decreasing cell migration and promoting macrophage entrapment in the vessel wall.
Activation of inflammatory pathways in the endothelium contributes to vascular diseases, including sepsis and atherosclerosis. We demonstrate that miR‐146a and miR‐146b are induced in endothelial ...cells upon exposure to pro‐inflammatory cytokines. Despite the rapid transcriptional induction of the miR‐146a/b loci, which is in part mediated by EGR‐3, miR‐146a/b induction is delayed and sustained compared to the expression of leukocyte adhesion molecules, and in fact coincides with the down‐regulation of inflammatory gene expression. We demonstrate that miR‐146 negatively regulates inflammation. Over‐expression of miR‐146a blunts endothelial activation, while knock‐down of miR‐146a/b in vitro or deletion of miR‐146a in mice has the opposite effect. MiR‐146 represses the pro‐inflammatory NF‐κB pathway as well as the MAP kinase pathway and downstream EGR transcription factors. Finally, we demonstrate that HuR, an RNA binding protein that promotes endothelial activation by suppressing expression of endothelial nitric oxide synthase (eNOS), is a novel miR‐146 target. Thus, we uncover an important negative feedback regulatory loop that controls pro‐inflammatory signalling in endothelial cells that may impact vascular inflammatory diseases.
miR‐146 microRNA is induced by proinflammatory cytokines and acts to inhibit vascular inflammation by repressing endothelial activation through the inhibition of both transcriptional and posttranscriptional endothelial proinflammatory pathways.
A
bstract
String theory has no parameter except the string scale
M
S
, so the Planck scale
M
Pl
, the supersymmetry-breaking scale
, the electroweak scale
m
EW
as well as the vacuum energy density ...(cosmological constant) Λ are to be determined dynamically at any local minimum solution in the string theory landscape. Here we consider a model that links the supersymmetric electroweak phenomenology (bottom up) to the string theory motivated flux compactification approach (top down). In this model, supersymmetry is broken by a combination of the racetrack Kähler uplift mechanism, which naturally allows an exponentially small positive Λ in a local minimum, and the anti-D3-brane in the KKLT scenario. In the absence of the Higgs doublets from the supersymmetric standard model, one has either a small Λ or a big enough
, but not both. The introduction of the Higgs fields (with their soft terms) allows a small Λ and a big enough
simultaneously. Since an exponentially small Λ is statistically preferred (as the properly normalized probability distribution
P
(Λ) diverges at Λ = 0
+
), identifying the observed Λ
obs
to the median value Λ
50%
yields
m
EW
∼
100 GeV. We also find that the warped anti-D3-brane tension has a SUSY-breaking scale
∼ 100
m
EW
while the SUSY-breaking scale that directly correlates with the Higgs fields in the visible sector is
≃
m
EW
.
OBJECTIVE—In response to tissue injury, the appropriate progression of events in angiogenesis is controlled by a careful balance between pro and antiangiogenic factors. We aimed to identify and ...characterize microRNAs that regulate angiogenesis in response to tissue injury.
APPROACH AND RESULTS—We show that in response to tissue injury, microRNA-615-5p (miR-615-5p) is rapidly induced and serves as an antiangiogenic microRNA by targeting endothelial cell VEGF (vascular endothelial growth factor)-AKT (protein kinase B)/eNOS (endothelial nitric oxide synthase) signaling in vitro and in vivo. MiR-615-5p expression is increased in wounds of diabetic db/db mice, in plasma of human subjects with acute coronary syndromes, and in plasma and skin of human subjects with diabetes mellitus. Ectopic expression of miR-615-5p markedly inhibited endothelial cell proliferation, migration, network tube formation in Matrigel, and the release of nitric oxide, whereas miR-615-5p neutralization had the opposite effects. Mechanistic studies using transcriptomic profiling, bioinformatics, 3′ untranslated region reporter and microribonucleoprotein immunoprecipitation assays, and small interfering RNA dependency studies demonstrate that miR-615-5p inhibits the VEGF-AKT/eNOS signaling pathway in endothelial cells by targeting IGF2 (insulin-like growth factor 2) and RASSF2 (Ras-associating domain family member 2). Local delivery of miR-615-5p inhibitors, markedly increased angiogenesis, granulation tissue thickness, and wound closure rates in db/db mice, whereas miR-615-5p mimics impaired these effects. Systemic miR-615-5p neutralization improved skeletal muscle perfusion and angiogenesis after hindlimb ischemia in db/db mice. Finally, modulation of miR-615-5p expression dynamically regulated VEGF-induced AKT signaling and angiogenesis in human skin organoids as a model of tissue injury.
CONCLUSIONS—These findings establish miR-615-5p as an inhibitor of VEGF-AKT/eNOS–mediated endothelial cell angiogenic responses and that manipulating miR-615-5p expression could provide a new target for angiogenic therapy in response to tissue injury.
A
bstract
Guided by the naturalness criterion for an exponentially small cosmological constant, we present a string theory motivated 4-dimensional
N
= 1 non-linear supergravity model (or its linear ...version with a nilpotent superfield) with spontaneous supersymmetry breaking. The model encompasses the minimal supersymmetric standard model, the racetrack Kähler uplift, and the KKLT anti-D3-branes, and use the nilpotent superfield to project out the undesirable interaction terms as well as the unwanted degrees of freedom to end up with the standard model (not the supersymmetric version) of strong and electroweak interactions.
To understand the molecular pathways underlying the cardiac preconditioning effect of short-term caloric restriction (CR).
Lifelong CR has been suggested to reduce the incidence of cardiovascular ...disease through a variety of mechanisms. However, prolonged adherence to a CR life-style is difficult. Here we reveal the pathways that are modulated by short-term CR, which are associated with protection of the mouse heart from ischemia.
Male 10-12 wk old C57bl/6 mice were randomly assigned to an ad libitum (AL) diet with free access to regular chow, or CR, receiving 30% less food for 7 days (d), prior to myocardial infarction (MI) via permanent coronary ligation. At d8, the left ventricles (LV) of AL and CR mice were collected for Western blot, mRNA and microRNA (miR) analyses to identify cardioprotective gene expression signatures. In separate groups, infarct size, cardiac hemodynamics and protein abundance of caspase 3 was measured at d2 post-MI.
This short-term model of CR was associated with cardio-protection, as evidenced by decreased infarct size (18.5±2.4% vs. 26.6±1.7%, N=10/group; P=0.01). mRNA and miR profiles pre-MI (N=5/group) identified genes modulated by short-term CR to be associated with circadian clock, oxidative stress, immune function, apoptosis, metabolism, angiogenesis, cytoskeleton and extracellular matrix (ECM). Western blots pre-MI revealed CR-associated increases in phosphorylated Akt and GSK3ß, reduced levels of phosphorylated AMPK and mitochondrial related proteins PGC-1α, cytochrome C and cyclooxygenase (COX) IV, with no differences in the levels of phosphorylated eNOS or MAPK (ERK1/2; p38). CR regimen was also associated with reduced protein abundance of cleaved caspase 3 in the infarcted heart and improved cardiac function.
Noncoding RNAs in Critical Limb Ischemia Pérez-Cremades, Daniel; Cheng, Henry S; Feinberg, Mark W
Arteriosclerosis, thrombosis, and vascular biology,
2020-March, Letnik:
40, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Peripheral artery disease, caused by chronic arterial occlusion of the lower extremities, affects over 200 million people worldwide. Peripheral artery disease can progress into critical limb ischemia ...(CLI), its more severe manifestation, which is associated with higher risk of limb amputation and cardiovascular death. Aiming to improve tissue perfusion, therapeutic angiogenesis held promise to improve ischemic limbs using delivery of growth factors but has not successfully translated into benefits for patients. Moreover, accumulating studies suggest that impaired downstream signaling of these growth factors (or angiogenic resistance) may significantly contribute to CLI, particularly under harsh environments, such as diabetes mellitus. Noncoding RNAs are essential regulators of gene expression that control a range of pathophysiologies relevant to CLI, including angiogenesis/arteriogenesis, hypoxia, inflammation, stem/progenitor cells, and diabetes mellitus. In this review, we summarize the role of noncoding RNAs, including microRNAs and long noncoding RNAs, as functional mediators or biomarkers in the pathophysiology of CLI. A better understanding of these ncRNAs in CLI may provide opportunities for new targets in the prevention, diagnosis, and therapeutic management of this disabling disease state.
Chronic activation of the innate immune system drives inflammation and contributes directly to atherosclerosis. We previously showed that macrophages in the atherogenic plaque undergo RIPK3 ...(receptor-interacting serine/threonine-protein kinase 3)-MLKL (mixed lineage kinase domain-like protein)-dependent programmed necroptosis in response to sterile ligands such as oxidized low-density lipoprotein and damage-associated molecular patterns and that necroptosis is active in advanced atherosclerotic plaques. Upstream of the RIPK3-MLKL necroptotic machinery lies RIPK1 (receptor-interacting serine/threonine-protein kinase 1), which acts as a master switch that controls whether the cell undergoes NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells)-dependent inflammation, caspase-dependent apoptosis, or necroptosis in response to extracellular stimuli. We therefore set out to investigate the role of RIPK1 in the development of atherosclerosis, which is driven largely by NF-κB-dependent inflammation at early stages. We hypothesize that, unlike RIPK3 and MLKL, RIPK1 primarily drives NF-κB-dependent inflammation in early atherogenic lesions, and knocking down RIPK1 will reduce inflammatory cell activation and protect against the progression of atherosclerosis.
We examined expression of RIPK1 protein and mRNA in both human and mouse atherosclerotic lesions, and used loss-of-function approaches in vitro in macrophages and endothelial cells to measure inflammatory responses. We administered weekly injections of RIPK1 antisense oligonucleotides to
mice fed a cholesterol-rich (Western) diet for 8 weeks.
We find that RIPK1 expression is abundant in early-stage atherosclerotic lesions in both humans and mice. Treatment with RIPK1 antisense oligonucleotides led to a reduction in aortic sinus and en face lesion areas (47.2% or 58.8% decrease relative to control,
<0.01) and plasma inflammatory cytokines (IL-1α interleukin 1α, IL-17A interleukin 17A,
<0.05) in comparison with controls.
knockdown in macrophages decreased inflammatory genes (NF-κB, TNFα tumor necrosis factor α, IL-1α) and in vivo lipopolysaccharide- and atherogenic diet-induced NF-κB activation. In endothelial cells, knockdown of
prevented NF-κB translocation to the nucleus in response to TNFα, where accordingly there was a reduction in gene expression of
,
, and monocyte attachment.
We identify RIPK1 as a central driver of inflammation in atherosclerosis by its ability to activate the NF-κB pathway and promote inflammatory cytokine release. Given the high levels of RIPK1 expression in human atherosclerotic lesions, our study suggests RIPK1 as a future therapeutic target to reduce residual inflammation in patients at high risk of coronary artery disease.
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