title: ASK1 mediates the teratogenicity of diabetes in the developing heart by inducing ER stress and inhibiting critical factors essential for cardiac development.
abstract: Maternal diabetes in mice induces heart defects similar to those observed in human diabetic pregnancies. Diabetes enhances apoptosis and suppresses cell proliferation in the developing heart, yet the underlying mechanism remains elusive. Apoptosis signal-regulating kinase 1 (ASK1) activates the proapoptotic c-Jun NH2-terminal kinase 1/2 (JNK1/2) leading to apoptosis, suggesting a possible role of ASK1 in diabetes-induced heart defects. We aimed to investigate whether ASK1 is activated in the heart and whether deleting the Ask1 gene blocks diabetes-induced adverse events and heart defect formation. The ASK1-JNK1/2 pathway was activated by diabetes. Deleting Ask1 gene significantly reduced the rate of heart defects, including ventricular septal defects (VSDs) and persistent truncus arteriosus (PTA). Additionally, Ask1 deletion diminished diabetes-induced JNK1/2 phosphorylation and its downstream transcription factors and endoplasmic reticulum (ER) stress markers. Consistent with this, caspase activation and apoptosis were blunted. Ask1 deletion blocked the increase in cell cycle inhibitors (p21 and p27) and the decrease in cyclin D1 and D3 and reversed diabetes-repressed cell proliferation. Ask1 deletion also restored the expression of BMP4, NKX2.5, and GATA5, Smad1/5/8 phosphorylation, whose mutations or deletion result in reduced cell proliferation, VSD, and PTA formation. We conclude that ASK1 may mediate the teratogenicity of diabetes through activating the JNK1/2-ER stress pathway and inhibiting cell cycle progression, thereby impeding the cardiogenesis pathways essential for ventricular septation and outflow tract development.
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences.
authors.forename: Yanqing
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Medicine, and.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Quon
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences.
authors.forename: Xuezheng
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Obstetrics, Gynecology, and Reproductive Sciences, Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland pyang@fpi.umaryland.edu.
authors.forename: Peixin
authors.initials: P
authors.lastname: Yang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D056743:Cyclin D3 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005260:Female; D050992:GATA5 Transcription Factor / Q000378:metabolism; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D006345:Heart Septal Defects, Ventricular / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D048056:Mitogen-Activated Protein Kinase 9 / Q000378:metabolism; D010766:Phosphorylation; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D051898:Smad1 Protein / Q000378:metabolism; D051902:Smad5 Protein / Q000378:metabolism; D051904:Smad8 Protein / Q000378:metabolism; D064793:Teratogenesis / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism; D014339:Truncus Arteriosus, Persistent / Q000209:etiology / Q000235:genetics* / Q000378:metabolism
chemical_list: C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; C530105:Ccnd1 protein, mouse; C534697:Ccnd3 protein, mouse; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D056743:Cyclin D3; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050992:GATA5 Transcription Factor; C494756:Gata5 protein, mouse; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D051904:Smad8 Protein; C491621:Smad9 protein, mouse; D014157:Transcription Factors; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse
keywords: apoptosis; apoptosis signal-regulating kinase 1; endoplasmic reticulum stress; heart defects; maternal diabetes