Obesity accelerates endothelial-to-mesenchymal transition in adipose tissues of mice and humans.

Introduction: Vascular dysfunction and chronic inflammation are characteristics of obesity-induced adipose tissue dysfunction. Proinflammatory cytokines can drive an endothelial-to-mesenchymal transition (EndoMT), where endothelial cells undergo a phenotypic switch to mesenchymal-like cells that are pro-inflammatory and pro-fibrotic. In this study, we sought to determine whether obesity can promote EndoMT in adipose tissue. Methods: Mice in which endothelial cells are lineage-traced with eYFP were fed a high-fat/high-sucrose (HF/HS) or Control diet for 13, 26, and 52 weeks, and EndoMT was assessed in adipose tissue depots as percentage of CD45-CD31-Acta2+ mesenchymal-like cells that were eYFP +. EndoMT was also assessed in human adipose endothelial cells through cell culture assays and by the analysis of single cell RNA sequencing datasets obtained from the visceral adipose tissues of obese individuals. Results: Quantification by flow cytometry showed that mice fed a HF/HS diet display a time-dependent increase in EndoMT over Control diet in subcutaneous adipose tissue (+3.0%, +2.6-fold at 13 weeks; +10.6%, +3.2-fold at 26 weeks; +11.8%, +2.9-fold at 52 weeks) and visceral adipose tissue (+5.5%, +2.3-fold at 13 weeks; +20.7%, +4.3-fold at 26 weeks; +25.7%, +4.8-fold at 52 weeks). Transcriptomic analysis revealed that EndoMT cells in visceral adipose tissue have enriched expression of genes associated with inflammatory and TGFß signaling pathways. Human adipose-derived microvascular endothelial cells cultured with TGF-ß1, IFN-γ, and TNF-α exhibited a similar upregulation of EndoMT markers and induction of inflammatory response pathways. Analysis of single cell RNA sequencing datasets from visceral adipose tissue of obese patients revealed a nascent EndoMT sub-cluster of endothelial cells with reduced PECAM1 and increased ACTA2 expression, which was also enriched for inflammatory signaling genes and other genes associated with EndoMT. Discussion: These experimental and clinical findings show that chronic obesity can accelerate EndoMT in adipose tissue. We speculate that EndoMT is a feature of adipose tissue dysfunction that contributes to local inflammation and the systemic metabolic effects of obesity..

Genetics of age-related clonal hematopoiesis and atherosclerotic cardiovascular disease.

PURPOSE OF REVIEW: While advanced age is the major risk factor for the development of atherosclerotic cardiovascular disease (ASCVD), we have a poor understanding of how aging promotes the progression of this disease. Recent evidence suggests that the age-dependent accumulation of somatic mutations in hematopoietic cells may represent a new causal risk factor for ASCVD. RECENT FINDINGS: A hallmark of aging is the accumulation of somatic DNA mutations in all tissues of the body. Accordingly, evidence shows that hematopoietic stem/progenitor cells accumulate somatic mutations as a function of age in nonsymptomatic individuals. When these mutations occur in driver genes that provide a selective advantage to the hematopoietic stem/progenitor cells, they undergo a clonal expansion and progressively give rise to blood leukocytes that harbor these mutations. This phenomenon, referred to as clonal hematopoiesis, has been associated with the increased risk of mortality, hematologic malignancy, ASCVD, and related diseases. Notably, many individuals exhibiting clonal hematopoiesis carry single 'driver' mutations in preleukemic genes including DNA methyltransferase 3a, ten-eleven translocation 2, additional sex combs like 1, and Janus kinase 2. Experimental studies show that these mutations in some of these genes can alter the inflammatory properties of the leukocyte and contribute to the pathogenesis of ASCVD. SUMMARY: We review recent epidemiological and experimental findings on the association between age-related clonal hematopoiesis and ASCVD by focusing on prevalent driver gene mutations.

Wnt5a-Mediated Neutrophil Recruitment Has an Obligatory Role in Pressure Overload-Induced Cardiac Dysfunction.

BACKGROUND: Although the complex roles of macrophages in myocardial injury are widely appreciated, the function of neutrophils in nonischemic cardiac pathology has received relatively little attention. METHODS: To examine the regulation and function of neutrophils in pressure overload-induced cardiac hypertrophy, mice underwent treatment with Ly6G antibody to deplete neutrophils and then were subjected to transverse aortic constriction. RESULTS: Neutrophil depletion diminished transverse aortic constriction-induced hypertrophy and inflammation and preserved cardiac function. Myeloid deficiency of Wnt5a, a noncanonical Wnt, suppressed neutrophil infiltration to the hearts of transverse aortic constriction-treated mice and produced a phenotype that was similar to the neutropenic conditions. Conversely, mice overexpressing Wnt5a in myeloid cells displayed greater hypertrophic growth, inflammation, and cardiac dysfunction. Neutrophil depletion reversed the Wnt5a overexpression-induced cardiac pathology and eliminated differences in cardiac parameters between wild-type and myeloid-specific Wnt5a transgenic mice. CONCLUSIONS: These findings reveal that Wnt5a-regulated neutrophil infiltration has a critical role in pressure overload-induced heart failure.

Comparative effectiveness of telemonitoring versus usual care for type 2 diabetes: A systematic review and meta-analysis.

AIMS: This study evaluated clinical effectiveness of telemonitoring on the management of patients with type 2 diabetes. METHODS: We searched Ovid-Medline, Ovid-EMBASE, and the Cochrane Library to identify randomized controlled trials that compared telemonitoring and usual care in patients with type 2 diabetes. RESULTS: Thirty-eight studies (6855 patients) were included. Telemonitoring was associated with a significant decrease in glycated haemoglobin levels compared to usual care (weighted mean difference -0.42%, 95% confidence interval -0.56 to -0.27) but there was evidence of heterogeneity (I2 = 96.9%). Telemonitoring was associated with a significant glycated haemoglobin reduction when biological data were transmitted through a web-based device weekly, when voice feedback was performed daily or immediately and when patients were provided with counselling. Telemonitoring also reduced glycated haemoglobin level in studies that monitored patients' medication adherence, provided counselling, education and alarm message. The rate of achieving glycated haemoglobin levels of < 7% was 1.8 times higher in the telemonitoring group compared to the usual care group (risk ratio 1.83, 95% confidence interval 1.35 to 2.47, I2 = 0%). There was also significant reduction in systolic blood pressure (weighted mean difference -1.33 mm Hg) and body mass index (weighted mean difference -0.25 kg/m2), but the clinical relevance of these results can be questioned. The data available on patient satisfaction, quality of life, medication adherence, prescription changes, stress and depression were limited. CONCLUSIONS: Telemonitoring interventions may be a better option than usual care in improving glycated haemoglobin control of patients with type 2 diabetes. Further studies should assess clinical benefit according to specific delivery modes of the intervention and patient-reported outcomes.

Simple and Biocompatible Ion Beam Micropatterning of a Cell-Repellent Polymer on Cell-Adhesive Surfaces to Manipulate Cell Adhesion.

In this paper, the simple and biocompatible micropatterning of cell-repellent poly(N-isopropylacrylamide) (PNIPAAm) on a cell-adhesive substrate by ion beam micropatterning to control cell adhesion is described. Cell-repellent PNIPAAm films spin-coated on cell-adhesive tissue culture polystyrene (TCPS) substrates were selectively irradiated by energetic proton ions at various fluences through a pattern mask, and subsequently developed to create the micropatterns of PNIPAAm. Well-defined negative-type PNIPAAm micropatterns were successfully created on the TCPS substrates at fluences higher than 5 x 10¹4 ions/cm², and their chemical properties were dependent on the fluence. Moreover, based on the results of the protein adsorption and in-vitro cell culture tests, 200 µm well-defined micropatterns of mammalian cells were clearly formed on the PNIPAAm-micropatterned TCPS substrates though the preferential adsorption and growth of cells on the TCPS regions due to the strong cell-repellency of PNIPAAm.

Patterning of gold nanoparticles on fluoropolymer films by using patterned surface grafting and layer-by-layer deposition techniques.

The patterning of gold nanoparticles (GNPs) on the surface of a fluoropolymer substrate by using patterned surface grafting and layer-by-layer deposition techniques is described. The surface of a poly(tetrafluoroethylene-co-perfluorovinyl ether) (PFA) substrate was selectively implanted with 150 keV proton ions. Peroxide groups were successfully formed on the implanted PFA surface, and their concentration depended on the fluence. Acrylic acid was graft polymerized onto the implanted regions of the PFA substrate, resulting in well-defined patterns of poly(acrylic acid) (PAA) on the PFA substrate. The surface properties of the PAA-patterned PFA surface, such as chemical compositions, wettability, and morphology, were investigated. The surface analysis results revealed that PAA was definitely present on the implanted regions of the PFA surface, and the degree of grafting was dependent on three factors: fluence, grafting time, and monomer concentration. Furthermore, GNP patterns were generated on the prepared PAA-patterned PFA surface by layer-by-layer deposition of GNPs and poly(diallyldimethyl ammonium chloride). The multilayers of GNPs were deposited only onto the PAA-grafted regions separated by bare PFA regions, and the resulting GNP patterns exhibited good electrical conductivity.

Higher circulating hsCRP levels are associated with lower bone mineral density in healthy pre- and postmenopausal women: evidence for a link between systemic inflammation and osteoporosis.

Factors involved in inflammation are linked with those critical for bone remodeling. We examined the association between serum high sensitivity C-reactive protein (hsCRP) levels and bone mineral density (BMD) in healthy women. Serum concentrations of hsCRP and total alkaline phosphatase (ALP) were measured in premenopausal ( n =3,662) and postmenopausal ( n =1,031) women aged 30 years or older. BMD was measured at the femoral neck and lumbar spine using dual energy X-ray absorptiometry. According to the WHO definition, osteopenia was diagnosed at -2.5< T -score < -1.0 SD, and osteoporosis was diagnosed at T -score < or = -2.5 SD at any sites. Compared with normal subjects, log-transformed serum hsCRP levels were higher in osteopenic and osteoporotic subjects (all, P < 0.001) with linearity ( P for trend <0.001), after adjustment for age, BMI and menopausal status. Menopausal status did not have a significant interaction on the association ( P =0.457). In both premenopausal and postmenopausal women, serum total ALP levels were higher in the subjects with higher hsCRP quintiles than those with the lowest quintile (all, P for trend < 0.001). Multivariate-adjusted odds ratio (OR) for osteoporosis and osteopenia were 1.35 (95% CI, 1.08 to 1.68) in the highest hsCRP quintile of premenopausal women, and OR for osteoporosis was 1.54 (95% CI, 1.10 to 2.53) in the highest hsCRP quintile of postmenopausal women. These findings suggest that subclinical systemic inflammation may be associated with bone turnover rate and bone mass in healthy women.