Bone Morphogenic Protein 4-Smad-Induced Upregulation of Platelet-Derived Growth Factor AA Impairs Endothelial Function.

OBJECTIVE: Bone morphogenic protein 4 (BMP4) is an important mediator of endothelial dysfunction in cardio-metabolic diseases, whereas platelet-derived growth factors (PDGFs) are major angiogenic and proinflammatory mediator, although the functional link between these 2 factors is unknown. The present study investigated whether PDGF mediates BMP4-induced endothelial dysfunction in diabetes mellitus. APPROACH AND RESULTS: We generated Ad-Bmp4 to overexpress Bmp4 and Ad-Pdgfa-shRNA to knockdown Pdgfa in mice through tail intravenous injection. SMAD4-shRNA lentivirus, SMAD1-shRNA, and SMAD5 shRNA adenovirus were used for knockdown in human and mouse endothelial cells. We found that PDGF-AA impaired endothelium-dependent vasodilation in aortas and mesenteric resistance arteries. BMP4 upregulated PDGF-AA in human and mouse endothelial cells, which was abolished by BMP4 antagonist noggin or knockdown of SMAD1/5 or SMAD4. BMP4-impared relaxation in mouse aorta was also ameliorated by PDGF-AA neutralizing antibody. Tail injection of Ad-Pdgfa-shRNA ameliorates endothelial dysfunction induced by Bmp4 overexpression (Ad-Bmp4) in vivo. Serum PDGF-AA was elevated in both diabetic patients and diabetic db/db mice compared with nondiabetic controls. Pdgfa-shRNA or Bmp4-shRNA adenovirus reduced serum PDGF-AA concentration in db/db mice. PDGF-AA neutralizing antibody or tail injection with Pdgfa-shRNA adenovirus improved endothelial function in aortas and mesenteric resistance arteries from db/db mice. The effect of PDGF-AA on endothelial function in mouse aorta was also inhibited by Ad-Pdgfra-shRNA to inhibit PDGFRα. CONCLUSIONS: The present study provides novel evidences to show that PDGF-AA impairs endothelium-dependent vasodilation and PDGF-AA mediates BMP4-induced adverse effect on endothelial cell function through SMAD1/5- and SMAD4-dependent mechanisms. Inhibition of PGDF-AA ameliorates vascular dysfunction in diabetic mice.

Targeting the platelet-derived growth factor signalling in cardiovascular disease.

Over 40 years of studies on platelet-derived growth factors (PDGFs) and their receptors, the molecular mechanisms and functional roles of PDGFs in the development of embryos and human diseases, especially in cancer, are gradually being unravelled. PDGF-BB was approved by the United States Food and Drug Administration for promoting wound healing, while imatinib, which selectively inhibits tyrosine kinase activity of PDGF receptors (PDGFR), has been prescribed to treat patients with gastrointestinal stromal tumor and chronic eosinophilic leukaemia. However, much less often have these drugs been studied in relation to cardiovascular diseases. This brief review mainly describes the role of PDGF signalling in cardiovascular pathogenesis such as atherosclerosis, pulmonary arterial hypertension, diabetes, angiogenesis and inflammation with an emphasis on how PDGFs function in these situations and what components might serve as potential therapeutic targets against cardio-metabolic dysfunction.

Microbiota-mediated shaping of mouse spleen structure and immune function characterized by scRNA-seq and Stereo-seq.

Gut microbes exhibit complex interactions with their hosts and shape an organism's immune system throughout its lifespan. As the largest secondary lymphoid organ, the spleen has a wide range of immunological functions. To explore the role of microbiota in regulating and shaping the spleen, we employ scRNA-seq and Stereo-seq technologies based on germ-free (GF) mice to detect differences in tissue size, anatomical structure, cell types, functions, and spatial molecular characteristics. We identify 18 cell types, 9 subtypes of T cells, and 7 subtypes of B cells. Gene differential expression analysis reveals that the absence of microorganisms results in alterations in erythropoiesis within the red pulp region and congenital immune deficiency in the white pulp region. Stereo-seq results demonstrate a clear hierarchy of immune cells in the spleen, including marginal zone (MZ) macrophages, MZ B cells, follicular B cells and T cells, distributed in a well-defined pattern from outside to inside. However, this hierarchical structure is disturbed in GF mice. Ccr7 and Cxcl13 chemokines are specifically expressed in the spatial locations of T cells and B cells, respectively. We speculate that the microbiota may mediate the structural composition or partitioning of spleen immune cells by modulating the expression levels of chemokines.

Physical Fitness of Chinese Primary School Students across the Coronavirus (COVID-19) Outbreak: A Retrospective Repeated Cross-Sectional Study.

Social distancing measures against COVID-19 imposed restrictions on students that may have affected their physical health and fitness. The objective of this study was to investigate the change in physical fitness of primary school students across the coronavirus outbreaks from 2019 to 2021. This was a retrospective repeated cross-sectional study. We obtained the annual physical and fitness assessment data measured every November for all students at the same primary school in Guangzhou, China. There was a total of 6371 observations in the dataset for three years. The physical fitness of the students was evaluated with an overall physical fitness score, body mass index (BMI), lung vital capacity, physical flexibility (via a sit-and-reach test) and sports task performances (sprint, shuttle run, rope-jumping, and sit-up). Generalised estimating equations were used to determine any significant changes from 2019 to 2021, adjusted for confounders. After the COVID-19 outbreak in 2021, there was a significant elevation in BMI of 0.64 kg/m2 in 2020 and 0.39 kg/m2 in 2021 (p < 0.001). The overall physical fitness score was significantly increased by 2.1 and 4.1 points, respectively, in 2020 and 2021 (p < 0.001). Lung vital capacity and rope-jumping performance were significantly improved in both 2020 and 2021 compared with 2019, and sit-up performance was marginally significantly improved in 2020 and significantly improved in 2021. However, students demonstrated poorer flexibility and sprint and shuttle run performance in 2021 compared with 2019. A health promotion programme during and after COVID-19, including online physical education classes, television broadcasts, and a rope-jumping campaign, could account for these positive outcomes, along with the ease of administering rope-jumping and sit-ups at home.

Role of platelet-derived growth factor in type II diabetes mellitus and its complications.

Type 2 diabetes mellitus is a type of metabolic disorder characterized by hyperglycaemia with multiple serious complications, such as diabetic neuropathies, diabetic nephropathy, diabetic retinopathy, and diabetic foot. Platelet-derived growth factors are growth factors that regulate cell growth and division, playing a critical role in diabetes and its harmful complications. This review focused on the cellular mechanism of platelet-derived growth factors and their receptors on diabetes development. Furthermore, we raise some proper therapeutic molecular targets for the treatment of diabetes and its complications.

NK cells induce hepatic ER stress to promote insulin resistance in obesity through osteopontin production.

High-fat diet (HFD) induced hepatic endoplasmic reticulum (ER) stress drives insulin resistance (IR) and steatosis. NK cells in adipose tissue play an important role in the pathogenesis of IR in obesity. Whether NK cells in the liver can induce hepatic ER stress and thus promote IR in obesity is still unknown. We demonstrate that HFD-fed mice display elevated production of proinflammatory cytokine osteopontin (OPN) in hepatic NK cells, especially in CD49a+ DX5- tissue-resident NK (trNK) cells. Obesity-induced ER stress, IR, and steatosis in the liver are ameliorated by ablating NK cells with neutralizing antibody in HFD-fed mice. OPN treatment enhances the expression of ER stress markers, including p-PERK, p-eIF2, ATF4, and CHOP in both murine liver tissues and HL-7702, a human liver cell line. Pretreatment of HL-7702 cells with OPN promotes hyperactivation of JNK and subsequent decrease of tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1), resulting in impaired insulin signaling, which can be reversed by inhibiting ER stress. Collectively, we demonstrate that hepatic NK cells induce obesity-induced hepatic ER stress, and IR through OPN production.

Zn-, Cd-, and Pb-transcription factor IIIA: properties, DNA binding, and comparison with TFIIIA-finger 3 metal complexes.

Properties of the metal ion binding sites of Zn-transcription factor IIIA (TFIIIA) were investigated to understand the potential of this type of zinc finger to undergo reactions that remove Zn(2+) from the protein. Zn-TFIIIA was purified from E. coli containing the cloned sequence for Xenopus laevis oocyte TFIIIA and its stoichiometry of bound Zn(2+) was shown to depend on the details of the isolation process. The average dissociation constant of Zn(2+) in Zn-TFIIIIA was 10(-7). The dissociation constant for Zn-F3, the third finger from the N-terminus of TFIIIA, was 1.0 x 10(-8). The reactivity of Zn-TFIIIA with a series of metal binding ligands, including 2-carboxy-2'-hydroxy-5'-sulfoformazylbenzene (zincon), 4-(2-pyridylazo)-resorcinol (PAR), and 3-ethoxy-2-oxo-butyraldehyde-bis-(N(4)-dimethylthiosemicarbazone) (H(2)KTSM(2)) revealed similar kinetics. The reactivity of PAR with Zn-TFIIIA declined substantially when the protein was bound to the internal control region (ICR) of the 5S ribosomal DNA. Both Cd(2+) and Pb(2+) disrupt TFIIIA binding to its cognate DNA sequence. The Pb(2+) dissociation constant of Pb-F3 was measured as 2.5 x 10(-8). According to NMR spectroscopy, F3 does not fold into a regular conformation in the presence of Pb(2+).