The Born in Guangzhou Cohort Study enables generational genetic discoveries.

Genomic research that targets large-scale, prospective birth cohorts constitutes an essential strategy for understanding the influence of genetics and environment on human health1. Nonetheless, such studies remain scarce, particularly in Asia. Here we present the phase I genome study of the Born in Guangzhou Cohort Study2 (BIGCS), which encompasses the sequencing and analysis of 4,053 Chinese individuals, primarily composed of trios or mother-infant duos residing in South China. Our analysis reveals novel genetic variants, a high-quality reference panel, and fine-scale local genetic structure within BIGCS. Notably, we identify previously unreported East Asian-specific genetic associations with maternal total bile acid, gestational weight gain and infant cord blood traits. Additionally, we observe prevalent age-specific genetic effects on lipid levels in mothers and infants. In an exploratory intergenerational Mendelian randomization analysis, we estimate the maternal putatively causal and fetal genetic effects of seven adult phenotypes on seven fetal growth-related measurements. These findings illuminate the genetic links between maternal and early-life traits in an East Asian population and lay the groundwork for future research into the intricate interplay of genetics, intrauterine exposures and early-life experiences in shaping long-term health.

Endothelial S1pr1 regulates pressure overload-induced cardiac remodelling through AKT-eNOS pathway.

Cardiac vascular microenvironment is crucial for cardiac remodelling during the process of heart failure. Sphingosine 1-phosphate (S1P) tightly regulates vascular homeostasis via its receptor, S1pr1. We therefore hypothesize that endothelial S1pr1 might be involved in pathological cardiac remodelling. In this study, heart failure was induced by transverse aortic constriction (TAC) operation. S1pr1 expression is significantly increased in microvascular endothelial cells (ECs) of post-TAC hearts. Endothelial-specific deletion of S1pr1 significantly aggravated cardiac dysfunction and deteriorated cardiac hypertrophy and fibrosis in myocardium. In vitro experiments demonstrated that S1P/S1pr1 praxis activated AKT/eNOS signalling pathway, leading to more production of nitric oxide (NO), which is an essential cardiac protective factor. Inhibition of AKT/eNOS pathway reversed the inhibitory effect of EC-S1pr1-overexpression on angiotensin II (AngII)-induced cardiomyocyte (CM) hypertrophy, as well as on TGF-ß-mediated cardiac fibroblast proliferation and transformation towards myofibroblasts. Finally, pharmacological activation of S1pr1 ameliorated TAC-induced cardiac hypertrophy and fibrosis, leading to an improvement in cardiac function. Together, our results suggest that EC-S1pr1 might prevent the development of pressure overload-induced heart failure via AKT/eNOS pathway, and thus pharmacological activation of S1pr1 or EC-targeting S1pr1-AKT-eNOS pathway could provide a future novel therapy to improve cardiac function during heart failure development.

Glucose, Insulin, and Lipids in Cord Blood of Neonates and Their Association with Birthweight: Differential Metabolic Risk of Large for Gestational Age and Small for Gestational Age Babies.

OBJECTIVES: To investigate the association of birthweight percentile with cord blood glucose, lipids, and insulin levels. STUDY DESIGN: Data obtained from 1522 newborns were included in the Born in Guangzhou Cohort study. The generalized additive model and multivariable linear regression model were used to explore the nonlinear and linear relationships between birthweight and cord blood metabolic measures, and to evaluate the differences of metabolic measures Z-scores among small for gestational age, appropriate for gestational age, and large for gestational age babies. RESULTS: Birthweight Z-score was linearly associated with increased cord blood insulin Z-score (adjusted ß = 0.30; 95% CI, 0.22-0.37). Compared with appropriate for gestational age babies, neonates born small for gestational age had significantly higher cord blood triglycerides Z-score (adjusted mean difference [MDadj], 0.60; 95% CI, 0.40-0.79) and lower cord blood insulin (MDadj, -0.37; 95% CI, -0.57 to -0.16), high-density lipoprotein cholesterol (MDadj, -0.34; 95% CI, -0.55 to -0.13), total cholesterol (MDadj, -0.26; 95% CI, -0.47 to -0.05), and low-density lipoprotein (MDadj, -0.23; 95% CI, -0.43 to -0.02) Z-scores, and neonates born large for gestational age had higher cord blood insulin Z-score (MDadj, 0.31; 95% CI, 0.09 to 0.52). CONCLUSIONS: Our findings support the hypothesis that babies born small for gestational age and large for gestational age are exposed to different intrauterine environments, which may contribute to altered fat accumulation patterns with implications for the risk of metabolic dysfunction later in life. There is a need to consider the development of tailored intervention strategies to prevent metabolic dysfunction in adult life for these babies.

Cell-Specific Effects of GATA (GATA Zinc Finger Transcription Factor Family)-6 in Vascular Smooth Muscle and Endothelial Cells on Vascular Injury Neointimal Formation.

Objective- Transcription factor GATA (GATA zinc finger transcription factor family)-6 is highly expressed in vessels and rapidly downregulated in balloon-injured carotid arteries and viral delivery of GATA-6 to the vessels limited the neointimal formation, however, little is known about its cell-specific regulation of in vivo vascular smooth muscle cell (VSMC) phenotypic state contributing to neointimal formation. This study aims to determine the role of vascular cell-specific GATA-6 in ligation- or injury-induced neointimal hyperplasia in vivo. Approach and Results- Endothelial cell and VSMC-specific GATA-6 deletion mice are generated, and the results indicate that endothelial cell-specific GATA-6 deletion mice exhibit significant decrease of VSMC proliferation and attenuation of neointimal formation after artery ligation and injury compared with the wild-type littermate control mice. PDGF (platelet-derived growth factor)-B is identified as a direct target gene, and endothelial cell-GATA-6-PDGF-B pathway regulates VSMC proliferation and migration in a paracrine manner which controls the neointimal formation. In contrast, VSMC-specific GATA-6 deletion promotes injury-induced VSMC transformation from contractile to proliferative synthetic phenotype leading to increased neointimal formation. CCN (cysteine-rich 61/connective tissue growth factor/nephroblastoma overexpressed family)-5 is identified as a novel target gene, and VSMC-specific CCN-5 overexpression in mice reverses the VSMC-GATA-6 deletion-mediated increased cell proliferation and migration and finally attenuates the neointimal formation. Conclusions- This study gives us a direct in vivo evidence of GATA-6 cell lineage-specific regulation of PDGF-B and CCN-5 on VSMC phenotypic state, proliferation and migration contributing to neointimal formation, which advances our understanding of in vivo neointimal hyperplasia, meanwhile also provides opportunities for future therapeutic interventions.

Dysfunctional endothelial-derived microparticles promote inflammatory macrophage formation via NF-кB and IL-1ß signal pathways.

BACKGROUND: Circulating endothelial-derived microparticles (EMPs) are reported to be increased in acute coronary syndrome (ACS). However, it remains unclear whether EMPs from dysfunctional endothelium participate in the initiation and progression of ACS and what the underlying mechanisms might be. METHODS: Plasma EMPs were measured in 22 patients with ACS and 20 control patients without coronary artery diseases. EMPs from dysfunctional human umbilical vein endothelial cells (HUVECs) stressed by serum-starvation or hypoxia were compared to the EMPs from healthy HUVECs. Confocal and fluorescent microscopy was used to visualize the incorporation of EMPs into monocytes and the translocation of NF-кB. Monocyte adhesion, cell proliferation, and phagocytosis were detected by PKH26 red fluorescent labelling, Ki67 immunostaining, and Sudan IV staining for uptake of oxidized low-density lipoprotein, respectively. RESULTS: Plasma EMPs was significantly increased in ACS patients compared to controls. EMPs were incorporated into monocytes and EMPs from stressed HUVECs produced more pro-inflammatory cytokines compared to vehicle control, which was depended on NF-кB and IL-1ß signal pathways. EMPs from dysfunctional endothelium promoted monocyte adherence via NF-кB and IL-1ß-mediated MCP-1 and CCR-5 signals, as well as proliferation via the NF-кB and IL-1ß-mediated Cyclin D1 signals. Finally, EMPs from dysfunctional endothelium showed greater promotion of macrophage phagocytosis forming foam cells to produce more pro-inflammatory cytokines. CONCLUSION: MPs might be involved in the inflammatory process in patients with ACS via NF-κB and IL-1ß-dependent signals. Targeting EMP-mediated inflammatory responses may be a promising therapeutic strategy to limit the progression of disease in ACS.

The Born in Guangzhou Cohort Study (BIGCS).

The Born in Guangzhou Cohort Study (BIGCS) is a large-scale prospective observational study investigating the role of social, biological and environmental influences on pregnancy and child health and development in an urban setting in southern China. Pregnant women who reside in Guangzhou and who attend Guangzhou Women and Children's Medical Center (GWCMC) for antenatal care in early pregnancy (<20 weeks' gestation) are eligible for inclusion. Study recruitment commenced in February 2012, with an overall participation rate of 76.3%. Study recruitment will continue until December 2018 to achieve the target sample size of 30,000 mother-child pairs. At 30 April 2016, a total of 75,422 questionnaires have been collected, while 14,696 live births have occurred with planned follow-up of cohort children until age 18 years. During the same period a total of 1,053,000 biological samples have been collected from participants, including maternal, paternal and infant blood, cord blood, placenta, umbilical cord, and maternal and infant stool samples. The dataset has been enhanced by record linkage to routine health and administrative records. We plan future record linkage to school enrolment and national examination records.

Maternal IGF1 and IGF1R polymorphisms and the risk of spontaneous preterm birth.

BACKGROUND: The insulin-like growth factor (IGF) pathway was involved in the occurrence of spontaneous preterm birth (SPTB), but little is known regarding the relationship between genetic variations in IGF pathway and the risk of SPTB. We aimed to investigate the associations of IGF1 rs972936 and IGF1 receptor (IGF1R) rs2229765 polymorphisms with SPTB risk in a Chinese population. METHOD: A total of 114 cases of SPTB and 250 controls of term delivery were included from Guangzhou Women and Children's Medical Center, China. The odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) were calculated using multivariate logistic regression. RESULTS: We found that the GA and GA/AA genotypes of IGF1 rs972936 were associated with an increased risk of SPTB, and the adjusted ORs (95% CI) were 1.74 (1.01-3.02) and 1.75 (1.04-2.93) respectively. Women carrying GA and GA/AA genotypes of IGF1R rs2229765 had a reduced risk compared to those with the GG genotype (0.60 [0.37-0.98] and 0.64 [0.40-1.00] respectively). There were significant interactions between IGF1 rs972936 and GDM status (P for interaction=.02), as well as between IGF1R rs2229765 and pre-pregnancy BMI (P for interaction <.001) on the risk of SPTB. CONCLUSION: Our findings suggest that polymorphisms of IGF1 rs972936 and IGF1R rs2229765 were associated with the risk of SPTB in Chinese pregnant women and these effects depend on the maternal metabolic status.

Antibiotic-induced depletion of Clostridium species increases the risk of secondary fungal infections in preterm infants.

Preterm infants or those with low birth weight are highly susceptible to invasive fungal disease (IFD) and other microbial or viral infection due to immaturity of their immune system. Antibiotics are routinely administered in these vulnerable infants in treatment of sepsis and other infectious diseases, which might cause perturbation of gut microbiome and hence development of IFD. In this study, we compared clinical characteristics of fungal infection after antibiotic treatment in preterm infants. As determined by 16S rRNA sequencing, compared with non-IFD patients with or without antibiotics treatment, Clostridium species in the intestinal tracts of patients with IFD were almost completely eliminated, and Enterococcus were increased. We established a rat model of IFD by intraperitoneal inoculation of C. albicans in rats pretreated with meropenem and vancomycin. After pretreatment with antibiotics, the intestinal microbiomes of rats infected with C. albicans were disordered, as characterized by an increase of proinflammatory conditional pathogens and a sharp decrease of Clostridium species and Bacteroides. Immunofluorescence analysis showed that C. albicans-infected rats pretreated with antibiotics were deficient in IgA and IL10, while the number of Pro-inflammatory CD11c+ macrophages was increased. In conclusion, excessive use of antibiotics promoted the imbalance of intestinal microbiome, especially sharp decreases of short-chain fatty acids (SCFA)-producing Clostridium species, which exacerbated the symptoms of IFD, potentially through decreased mucosal immunomodulatory molecules. Our results suggest that inappropriate use of broad-spectrum antibiotics may promote the colonization of invasive fungi. The results of this study provide new insights into the prevention of IFD in preterm infants.

Endothelial S1pr2 regulates post-ischemic angiogenesis via AKT/eNOS signaling pathway.

Aims: It is important to understand the mechanism that regulates post-ischemic angiogenesis and to explore a new therapeutic target for an effective improvement of revascularization in peripheral artery disease (PAD) patients. Post-ischemic angiogenesis is a highly orchestrated process, which involves vascular endothelial cells (ECs) proliferation, migration and assembly into capillaries. We found a significant reduction of S1pr2 (sphingosine 1-phosphate receptor 2) in endothelial cells after hindlimb ischemia (HLI). We thus hypothesized that EC-S1pr2 might be involved in the regulation of post-ischemic angiogenesis and blood flow recovery during peripheral arterial disease (PAD). Methods and Results: We generated both EC-specific S1pr2 loss-of-function and S1pr2 gain-of-function mice. Our study showed that EC-specific S1pr2 loss-of-function significantly enhanced post-ischemic angiogenesis and improved blood flow recovery upon femoral artery ligation, whereas the EC-specific S1pr2 gain-of-function severely hindered post-ischemic angiogenesis and reduced blood flow recovery in ischemic limbs. We next identified that S1pr2 inhibited AKT/eNOS signaling pathway, and thus inhibited EC proliferation/migration and angiogenic activity. As expected, pharmacological inhibition of S1pr2 by JTE013 improved post-ischemic angiogenesis and improved blood flow perfusion after femoral artery ligation. Moreover, we developed RGD-peptide magnetic nanoparticles packaging S1pr2-siRNA which specifically targeted ECs and achieved an efficient silencing of S1pr2 expression in ECs in vivo. This EC-targeted strategy to dampen S1pr2 significantly enhanced post-ischemic angiogenesis and boosted blood perfusion after HLI, supplying a novel therapy target for patients with peripheral arterial disease. Conclusions: This present study demonstrates that EC-expressing S1pr2 tightly controls post-ischemic angiogenesis and blood flow perfusion recovery. This research provides a novel strategy for EC-target knockdown of S1pr2 as a new therapeutic intervention for patients with peripheral artery disease.

Association of maternal lipid levels with birth weight and cord blood insulin: a Bayesian network analysis.

OBJECTIVE: To assess the independent association of maternal lipid levels with birth weight and cord blood insulin (CBI) level. SETTING: The Born in Guangzhou Cohort Study, Guangzhou, China. PARTICIPANTS: Women who delivered between January 2015 and June 2016 and with umbilical cord blood retained were eligible for this study. Those with prepregnancy health conditions, without an available fasting blood sample in the second trimester, or without demographic and glycaemic information were excluded. After random selection, data from 1522 mother-child pairs were used in this study. EXPOSURES AND OUTCOME MEASURES: Additive Bayesian network analysis was used to investigate the interdependency of lipid profiles with other metabolic risk factors (prepregnancy body mass index (BMI), fasting glucose and early gestational weight gain) in association with birth weight and CBI, along with multivariable linear regression models. RESULTS: In multivariable linear regressions, maternal triglyceride was associated with increased birth weight (adjusted ß=67.46, 95% CI 41.85 to 93.06 g per mmol/L) and CBI (adjusted ß=0.89, 95% CI 0.06 to 1.72 µU/mL per mmol/L increase), while high-density lipoprotein cholesterol was associated with decreased birth weight (adjusted ß=-45.29, 95% CI -85.49 to -5.09 g per mmol/L). After considering the interdependency of maternal metabolic risk factors in the Network analysis, none of the maternal lipid profiles was independently associated with birth weight and CBI. Instead, prepregnancy BMI was the global strongest factor for birth weight and CBI directly and indirectly. CONCLUSIONS: Gestational dyslipidaemia appears to be secondary to metabolic dysfunction with no clear association with metabolic adverse outcomes in neonates. Maternal prepregnancy overweight/obesity appears the most influential upstream metabolic risk factor for both maternal and neonatal metabolic health; these data imply weight management may need to be addressed from the preconception period and during early pregnancy.

Associations of Cord Blood Lipids with Childhood Adiposity at the Age of Three Years: A Prospective Birth Cohort Study.

We aimed to examine the associations between cord blood lipids and childhood adiposity and to investigate whether these associations vary across birth weight categories (small for gestational age (SGA), appropriate for gestational age (AGA) and large for gestational age (LGA)) in 1306 infants in the Born in Guangzhou Cohort Study, China. Adiposity outcomes at the age of three years included z-scores of weight-for-length/height (WFLZ), body mass index (BMIZ), subscapular (SSTZ) and triceps skinfold thickness (TSTZ), and the sum of skinfold thicknesses (SSFTZ). Cord blood triglycerides (TG) levels were negatively associated with WFLZ and BMIZ, whereas high density lipoprotein (HDL) levels were positively associated with WFLZ, BMIZ, TSTZ and SSFTZ. These associations were attenuated after adjustment for birth weight. Stratified analyses revealed that total cholesterol (TC) and low-density lipoprotein (LDL) levels were positively associated with childhood adiposity indicators among AGA infants but tended to be negatively associated with the adiposity indicators among LGA infants (p values for interaction <0.05). Furthermore, TG levels appeared to be positively associated with adiposity indicators among SGA infants but negatively associated with the outcomes among LGA infants (p values for interaction <0.05). Cord blood lipids levels might be associated with childhood adiposity, and these associations appear to differ across different birth weight categories. If confirmed in future studies, our findings suggest that individualized management plans might be warranted in preventing obesity.

Nano-CeO2 exhibits adverse effects at environmental relevant concentrations.

Ceria nanoparticles (nano-CeO(2)), due to their widespread applications, have attracted a lot of concern about their toxic effects on both human health and the environment. The present work aimed to evaluate the in vivo effects of nano-CeO(2) (8.5 nm) on Caenorhabditis elegans (C. elegans) at environmental relevant concentrations (molar concentrations ranging from 1 nM to 100 nM). The results indicate that nano-CeO(2) could induce ROS accumulation and oxidative damage in C. elegans, and finally lead to a decreased lifespan. The most surprising thing is that the mean lifespan of nematodes was significantly decreased by 12% even at the exposure level of 1 nM (p < 0.01). In vitro tests suggest that the ability of nano-CeO(2) to catalyze ROS generation was involved in the mechanism for its toxicity to C. elegans. To our best knowledge, this is the first case in which nanoparticles exhibit adverse effects on organisms at such low concentrations (1nM-100 nM). So, our findings indicate the importance of nanotoxicological investigations at environmentally relevant concentrations and will attract more attentions on the risks of NPs exposure.

Comparison study on the antibacterial activity of nano- or bulk-cerium oxide.

Due to the unique physical and chemical properties, nanosized cerium oxide (n-CeO2) has attracted considerable interest in many fields of research. The potential, the growing use and the mass production of n-CeO2 have stimulated research on their potential impact on the environment and human health. However, the toxicological definition for CeO2 nanoparticles (NPs) is still quite controversial. In the present work, we evaluated the antibacterial activity of CeO2 NPs sized ca. 7 nm (7-CeO2), ca. 25 nm (25-CeO2) and their bulk counterpart (b-CeO2), using gram-negative Escherichia coli (E. coli). Our results suggest that all the three types of CeO2 particles have antibacterial activity, and both the NPs are more toxic than b-CeO2. The rise in intracellular ROS level induced by direct contact of particles with the surface of E. coli was involved in the mechanism for the antibacterial activity of CeO2 NPs. Exposure to 25-CeO2 could also impair the integrity of the outer membrane within E. coli cells. Due to agglomeration and negligible effect on membrane integrity, 7-CeO2 did not exhibit greater antibacterial activity than 25-CeO2.

Identification of maternal continuous glucose monitoring metrics related to newborn birth weight in pregnant women with gestational diabetes.

PURPOSE: To identify the specific glucose metrics derived from maternal continuous glucose monitoring (CGM) data, which were associated with a higher percentile of offspring birth weight. METHODS: In this cohort study, we recruited singleton pregnant women with GDM who underwent CGM for 5-14 days at a mean of 28.8 gestational weeks between Jan 2017 and Nov 2018. Commonly used single summary glucose metrics of glucose exposure (including mean 24-h, daytime, and nighttime glucose level) and variability (including J-index and mean amplitude of glycaemic excursions) were derived from CGM data. A novel comprehensive glucose metric-hours per-day spent in a severe variability glucose mode (HSSV)-was identified using the spectral clustering method, which reflects both glucose level and variability. Multiple linear regression models were used to estimate the associations of sex- and gestational age-adjusted birth weight percentile with CGM parameters. RESULTS: Ninety-seven women comprising 127,279 glucose measurements were included. Each 1-SD increase in maternal nighttime mean glucose level and HSSV was associated with 6.0 (95% CI 0.4, 11.5) and 6.3 (95% CI 0.4, 12.2) percentage points increase in birth weight percentile, respectively. No associations were found between other glucose metrics and birth weight percentile. CONCLUSION: Nighttime mean glucose level has a comparable effect size to HSSV in association with fetal growth, suggesting that endogenous hyperglycemia might drive the association between maternal hyperglycemia and birth weight. Further studies need to examine the effect of lowering nighttime glucose level and/or HSSV on preventing fetal overgrowth in GDM women.

Associations of Longitudinal Fetal Growth Patterns With Cardiometabolic Factors at Birth.

Background: Birth weight is associated with cardiometabolic factors at birth. However, it is unclear when these associations occur in fetal life. We aimed to investigate the associations between fetal growth in different gestational periods and cord blood cardiometabolic factors. Methods: We included 1,458 newborns from the Born in Guangzhou Cohort Study, China. Z-scores of fetal size parameters [weight, abdominal circumference (AC), and femur length (FL)] at 22 weeks and growth at 22-27, 28-36, and ≥37 weeks were calculated from multilevel linear spline models. Multiple linear regression was used to examine the associations between fetal growth variables and z-scores of cord blood cardiometabolic factors. Results: Fetal weight at each period was positively associated with insulin levels, with stronger association at 28-36 weeks (ß, 0.31; 95% CI, 0.23 to 0.39) and ≥37 weeks (ß, 0.15; 95% CI, 0.10 to 0.20) compared with earlier gestational periods. Fetal weight at 28-36 (ß, -0.32; 95% CI, -0.39 to -0.24) and ≥37 weeks (ß, -0.26; 95% CI, -0.31 to -0.21) was negatively associated with triglyceride levels, whereas weight at 28-36 weeks was positively associated with HDL levels (ß, 0.12; 95% CI, 0.04 to 0.20). Similar results were observed for AC. Fetal FL at 22 and 22-27 weeks was associated with increased levels of insulin, glucose, and HDL. Conclusions: Fetal growth at different gestational periods was associated with cardiometabolic factors at birth, suggesting that an interplay between fetal growth and cardiometabolic factors might exist early in pregnancy.

Vascular endothelial S1pr1 ameliorates adverse cardiac remodelling via stimulating reparative macrophage proliferation after myocardial infarction.

AIMS: Endothelial cell (EC) homoeostasis plays an important role in normal physiological cardiac functions, and its dysfunction significantly influences pathological cardiac remodelling after myocardial infarction (MI). It has been shown that the sphingosine 1-phosphate receptor 1 (S1pr1) was highly expressed in ECs and played an important role in maintaining endothelial functions. We thus hypothesized that the endothelial S1pr1 might be involved in post-MI cardiac remodelling. METHODS AND RESULTS: Our study showed that the specific loss of endothelial S1pr1 exacerbated post-MI cardiac remodelling and worsened cardiac dysfunction. We found that the loss of endothelial S1pr1 significantly reduced Ly6clow macrophage accumulation, which is critical for the resolution of inflammation and cardiac healing following MI. The reduced reparative macrophages in post-MI myocardium contributed to the detrimental effects of endothelial S1pr1 deficiency on post-MI cardiac remodelling. Further investigations showed that the loss of endothelial S1pr1-reduced Ly6clow macrophage proliferation, while the pharmacological activation of S1pr1-enhanced Ly6clow macrophage proliferation, thereby ameliorated cardiac remodelling after MI. A mechanism study showed that S1P/S1pr1 activated the ERK signalling pathway and enhanced colony-stimulating factor 1 (CSF1) expression, which promoted Ly6clow macrophage proliferation in a cell-contact manner. The blockade of CSF1 signalling reversed the enhancing effect of S1pr1 activation on Ly6clow macrophage proliferation and worsened post-MI cardiac remodelling. CONCLUSION: This study reveals that cardiac microvascular endothelium promotes reparative macrophage proliferation in injured hearts via the S1P/S1PR1/ERK/CSF1 pathway and thus ameliorates post-MI adverse cardiac remodelling.

Endothelial Klf2-Foxp1-TGFß signal mediates the inhibitory effects of simvastatin on maladaptive cardiac remodeling.

Aims: Pathological cardiac fibrosis and hypertrophy are common features of left ventricular remodeling that often progress to heart failure (HF). Endothelial cells (ECs) are the most abundant non-myocyte cells in adult mouse heart. Simvastatin, a strong inducer of Krüppel-like Factor 2 (Klf2) in ECs, ameliorates pressure overload induced maladaptive cardiac remodeling and dysfunction. This study aims to explore the detailed molecular mechanisms of the anti-remodeling effects of simvastatin. Methods and Results: RGD-magnetic-nanoparticles were used to endothelial specific delivery of siRNA and we found absence of simvastatin's protective effect on pressure overload induced maladaptive cardiac remodeling and dysfunction after in vivo inhibition of EC-Klf2. Mechanism studies showed that EC-Klf2 inhibition reversed the simvastatin-mediated reduction of fibroblast proliferation and myofibroblast formation, as well as cardiomyocyte size and cardiac hypertrophic genes, which suggested that EC-Klf2 might mediate the anti-fibrotic and anti-hypertrophy effects of simvastatin. Similar effects were observed after Klf2 inhibition in cultured ECs. Moreover, Klf2 regulated its direct target gene TGFß1 in ECs and mediated the protective effects of simvastatin, and inhibition of EC-Klf2 increased the expression of EC-TGFß1 leading to simvastatin losing its protective effects. Also, EC-Klf2 was found to regulate EC-Foxp1 and loss of EC-Foxp1 attenuated the protective effects of simvastatin similar to EC-Klf2 inhibition. Conclusions: We conclude that cardiac microvasculature ECs are important in the modulation of pressure overload induced maladaptive cardiac remodeling and dysfunction, and the endothelial Klf2-TGFß1 or Klf2-Foxp1-TGFß1 pathway mediates the preventive effects of simvastatin. This study demonstrates a novel mechanism of the non-cholesterol lowering effects of simvastatin for HF prevention.

Maternal circulating leptin profile during pregnancy and gestational diabetes mellitus.

AIMS: To evaluate the difference in maternal circulating leptin profile between pregnant women with and without gestational diabetes mellitus (GDM). METHODS: This is a nested case-control study embedded in the Born in Guangzhou Cohort Study in Guangzhou Women and Children's Medical Center, with 198 GDM cases and 192 controls included. Maternal plasma leptin profile was defined as leptin concentrations measured at early (baseline) and late pregnancy, as well as a ratio of concentration at late to that at early pregnancy (RL1L0). General linear regression was used to assess the associations between GDM and log-transformed leptin measurements. RESULTS: Women with GDM had a higher baseline leptin concentration and lower RL1L0 compared to those without GDM. The log leptin concentration at baseline (ß: 0.19, 95%CI: 0.04, 0.34) and the log RL1L0 (ß: -0.22, 95%CI: -0.41, -0.03) were associated with GDM status. The RL1L0 decreased significantly along with the increase of 1-hour glucose and the difference between 1-hour and fasting glucose levels in both GDM and non-GDM women. CONCLUSIONS: Women with GDM had a certain profile of circulating leptin, with higher baseline concentration but less increase during pregnancy, suggesting an impaired compensatory response to increasing insulin resistance along with the progress of pregnancy.

Corrigendum: Germline-Encoded TCR-MHC Contacts Promote TCR V Gene Bias in Umbilical Cord Blood T Cell Repertoire.

[This corrects the article DOI: 10.3389/fimmu.2019.02064.].

Single-cell RNA-seq unveils critical regulators of human FOXP3+ regulatory T cell stability.

The heterogeneity and plasticity of T lymphocytes is critical for determining immune response outcomes. Functional regulatory T (Treg) cells are commonly characterized by stable FOXP3 expression and have reported to exhibit heterogeneous phenotypes under inflammatory conditions. However, the interplay between inflammation and Treg cell suppressive activity still remains elusive. Here, we utilized single-cell RNA sequencing to investigate how human Treg cells respond to the pro-inflammatory cytokine interleukin-6 (IL-6). We observed that Treg cells divided into two subpopulations after IL-6 stimulation. TIGIT- unstable Treg cells lost FOXP3 expression and gained an effector-like T cell phenotype, whereas TIGIT+ Treg cells retained robust suppressive function. Single cell transcriptome analysis revealed a spectrum of cellular states of IL-6-stimulated Treg cells and how cytochrome P450 family 1 subfamily A member 1 (CYP1A1) is a crucial regulator of Treg cell suppressive capability and stability. CYP1A1-deficient human Treg cells developed a Th17-like phenotype after IL-6 stimulation. Our findings implicate CYP1A1 as a previously unidentified regulator of Treg cells that may have target potential for clinical application for biotherapies.