English Journal

Aldose reductase drives hyperacetylation of egr-1 in hyperglycemia and consequent upregulation of proinflammatory and prothrombotic signals.

Vedantham S, Thiagarajan D, Ananthakrishnan R, Wang L, Rosario R, Zou YS, Goldberg I, Yan SF, Schmidt AM, Ramasamy R.Author information Diabetes Research Program, Department of Medicine, New York University Langone Medical Center, New York, NY.AbstractSustained increases in glucose flux via the aldose reductase (AR) pathway have been linked to diabetic vascular complications. Previous studies revealed that glucose flux via AR mediates endothelial dysfunction and leads to lesional hemorrhage in diabetic human AR (hAR) expressing mice in an apoE(-/-) background. Our studies revealed sustained activation of Egr-1 with subsequent induction of its downstream target genes tissue factor (TF) and vascular cell adhesion molecule-1 (VCAM-1) in diabetic apoE(-/-)hAR mice aortas and in high glucose-treated primary murine aortic endothelial cells expressing hAR. Furthermore, we observed that flux via AR impaired NAD(+) homeostasis and reduced activity of NAD(+)-dependent deacetylase Sirt-1 leading to acetylation and prolonged expression of Egr-1 in hyperglycemic conditions. In conclusion, our data demonstrate a novel mechanism by which glucose flux via AR triggers activation, acetylation, and prolonged expression of Egr-1 leading to proinflammatory and prothrombotic responses in diabetic atherosclerosis.
Diabetes.Diabetes.2014 Feb;63(2):761-74. doi: 10.2337/db13-0032. Epub 2013 Nov 1.
Sustained increases in glucose flux via the aldose reductase (AR) pathway have been linked to diabetic vascular complications. Previous studies revealed that glucose flux via AR mediates endothelial dysfunction and leads to lesional hemorrhage in diabetic human AR (hAR) expressing mice in an apoE(-/
PMID 24186862

CHD5 is required for spermiogenesis and chromatin condensation.

Zhuang T1, Hess RA2, Kolla V1, Higashi M1, Raabe TD3, Brodeur GM4.Author information 1Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States.2Department of Comparative Biosciences, College of Veterinary Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61802, United States.3Penn Gene Targeting Service, University of Pennsylvania, Philadelphia, PA 19104, United States.4Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, United States; The Department of Pediatrics, Perelman School of Medicine, Philadelphia, PA 19104, United States. Electronic address: Brodeur@email.chop.edu.AbstractHaploid spermatids undergo extensive cellular, molecular and morphological changes to form spermatozoa during spermiogenesis. Abnormalities in these steps can lead to serious male fertility problems, from oligospermia to complete azoospermia. CHD5 is a chromatin-remodeling nuclear protein expressed almost exclusively in the brain and testis. Male Chd5 knockout (KO) mice have deregulated spermatogenesis, characterized by immature sloughing of spermatids, spermiation failure, disorganization of the spermatogenic cycle and abnormal head morphology in elongating spermatids. This results in the inappropriate placement and juxtaposition of germ cell types within the epithelium. Sperm that did enter the epididymis displayed irregular shaped sperm heads, and retained cytoplasmic components. These sperm also stained positively for acidic aniline, indicating improper removal of histones and lack of proper chromatin condensation. Electron microscopy showed that spermatids in the seminiferous tubules of Chd5 KO mice have extensive nuclear deformation, with irregular shaped heads of elongated spermatids, and lack the progression of chromatin condensation in an anterior-to-posterior direction. However, the mRNA expression levels of other important genes controlling spermatogenesis were not affected. Chd5 KO mice also showed decreased H4 hyperacetylation beginning at stage IX, step 9, which is vital for the histone-transition protein replacement in spermiogenesis. Our data indicate that CHD5 is required for normal spermiogenesis, especially for spermatid chromatin condensation.
Mechanisms of development.Mech Dev.2014 Feb;131:35-46. doi: 10.1016/j.mod.2013.10.005. Epub 2013 Nov 16.
Haploid spermatids undergo extensive cellular, molecular and morphological changes to form spermatozoa during spermiogenesis. Abnormalities in these steps can lead to serious male fertility problems, from oligospermia to complete azoospermia. CHD5 is a chromatin-remodeling nuclear protein expressed
PMID 24252660

Valproic acid inhibits tumor angiogenesis in mice transplanted with Kasumi‑1 leukemia cells.

Zhang ZH1, Hao CL1, Liu P2, Tian X3, Wang LH1, Zhao L1, Zhu CM1.Author information 1Affiliated Hospital of Chengde Medical College, Chengde, Hebei 067000, P.R. China.2The First Hospital of Shijiazhuang City, Shijiazhuang, Hebei 050000, P.R. China.3Chinese PLA 89 Hospital, Weifang, Shandong 261000, P.R. China.AbstractHistone deacetylase (HDAC) inhibitors have been reported to inhibit tumor angiogenesis via the downregulation of angiogenic factors. Our previous in vitro studies demonstrated that valproic acid (VPA) exerted antitumor effects on Kasumi‑1 cells, which are human acute myeloid leukemia cells with an 8;21 chromosome translocation. In the present study, the effects of VPA on tumor angiogenesis were investigated in mice transplanted with Kasumi‑1 cells. Semi‑quantitative reverse transcription‑polymerase chain reaction, western blotting and immunohistochemistry were used to detect the expression of vascular endothelial growth factor (VEGF), VEGF receptor (VEGFR2) and basic fibroblast growth factor (bFGF). The tumor microvessel density was measured following staining with an anti‑CD34 antibody. Chromatin immunoprecipitation was used to study the effect of VPA‑induced histone hyperacetylation on VEGF transcription. An intraperitoneal injection of VPA inhibited tumor growth and angiogenesis in mice transplanted with Kasumi‑1 cells. The mRNA and protein expression of VEGF, VEGFR2 and bFGF were inhibited by VPA treatment. In addition, VPA downregulated HDAC, increased histone H3 acetylation and enhanced the accumulation of hyperacetylated histone H3 on the VEGF promoters. The findings of the present study indicate that VPA, an HDAC inhibitor, exerts an antileukemic effect through an anti‑angiogenesis mechanism. In conclusion, the mechanism underlying VPA‑induced anti‑angiogenesis is associated with the suppression of angiogenic factors and their receptors. VPA may increase the accumulation of acetylated histones on the VEGF promoters, which possibly contributes to the regulation of angiogenic factors.
Molecular medicine reports.Mol Med Rep.2014 Feb;9(2):443-9. doi: 10.3892/mmr.2013.1834. Epub 2013 Nov 28.
Histone deacetylase (HDAC) inhibitors have been reported to inhibit tumor angiogenesis via the downregulation of angiogenic factors. Our previous in vitro studies demonstrated that valproic acid (VPA) exerted antitumor effects on Kasumi‑1 cells, which are human acute myeloid leukemia cells with a
PMID 24297248