title: Induction of high mobility group-I(Y) protein by endotoxin and interleukin-1beta in vascular smooth muscle cells. Role in activation of inducible nitric oxide synthase.
abstract: Nonhistone chromosomal proteins of the high mobility group (HMG) affect the transcriptional regulation of certain mammalian genes. For example, HMG-I(Y) controls cytokine-mediated promoters that require transcription factors, such as nuclear factor-kappaB, for maximal expression. Even though a great deal is known about how HMG-I(Y) facilitates expression of other genes, less is known about the regulation of HMG-I(Y) itself, especially in cells in primary culture. Therefore we investigated the effect of endotoxin and the cytokine interleukin-1beta on HMG-I(Y) expression in vascular smooth muscle cells. Induction of HMG-I(Y) peaked after 48 h of interleukin-1beta stimulation (6.2-fold) in cells in primary culture, and this increase in mRNA corresponded to an increase in HMG-I(Y) protein. Moreover, immunohistochemical staining revealed a dramatic increase in HMG-I(Y) protein expression in vascular smooth muscle cells after endotoxin stimulation in vivo. This increase in HMG-I(Y) expression (both in vitro and in vivo) mirrored an up-regulation of inducible nitric oxide synthase, a cytokine-responsive gene. The functional significance of this coinduction is underscored by our finding that HMG-I(Y) potentiated the response of inducible nitric oxide synthase to nuclear factor-kappaB transactivation. Taken together, these studies suggest that induction of HMG-I(Y), and subsequent transactivation of iNOS, may contribute to a reduction in vascular tone during endotoxemia and other systemic inflammatory processes.
authors.affiliation: Cardiovascular Biology Laboratory, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: A
authors.initials: A
authors.lastname: Pellacani
authors.forename: M T
authors.initials: MT
authors.lastname: Chin
authors.forename: P
authors.initials: P
authors.lastname: Wiesel
authors.forename: M
authors.initials: M
authors.lastname: Ibanez
authors.forename: A
authors.initials: A
authors.lastname: Patel
authors.forename: S F
authors.initials: SF
authors.lastname: Yet
authors.forename: C M
authors.initials: CM
authors.lastname: Hsieh
authors.forename: J D
authors.initials: JD
authors.lastname: Paulauskis
authors.forename: R
authors.initials: R
authors.lastname: Reeves
authors.forename: M E
authors.initials: ME
authors.lastname: Lee
authors.forename: M A
authors.initials: MA
authors.lastname: Perrella
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004214:Distamycins / Q000494:pharmacology; D004330:Drosophila; D004789:Enzyme Activation; D004790:Enzyme Induction; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D025741:HMGA1a Protein; D006609:High Mobility Group Proteins / Q000096:biosynthesis*; D007375:Interleukin-1 / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D016676:Macrophages, Alveolar / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000096:biosynthesis*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D004214:Distamycins; D006609:High Mobility Group Proteins; D007375:Interleukin-1; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D025741:HMGA1a Protein; C030000:stallimycin; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat