Gene expression of cyclin-dependent kinase inhibitors and effect of heparin on their expression in mice with hypoxia-induced pulmonary hypertension.
The balance between cell proliferation and cell quiescence is regulated delicately by a variety of mediators, in which cyclin-dependent kinases (CDK) and CDK inhibitors (CDKI) play a very important role. Heparin which inhibits pulmonary artery smooth muscle cell (PASMC) proliferation increases the levels of two CDKIs, p21 and p27, although only p27 is important in inhibition of PASMC growth in vitro and in vivo. In the present study we investigated the expression profile of all the cell cycle regulating genes, including all seven CDKIs (p21, p27, p57, p15, p16, p18, and p19), in the lungs of mice with hypoxia-induced pulmonary hypertension. A cell cycle pathway specific gene microarray was used to profile the 96 genes involved in cell cycle regulation. We also observed the effect of heparin on gene expression. We found that (a) hypoxic exposure for two weeks significantly inhibited p27 expression and stimulated p18 activity, showing a 98% decrease in p27 and 81% increase in p18; (b) other CDKIs, p21, p57, p15, p16, and p19 were not affected significantly in response to hypoxia; (c) heparin treatment restored p27 expression, but did not influence p18; (d) ERK1/2 and p38 were mediators in heparin upregulation of p27. This study provides an expression profile of cell cycle regulating genes under hypoxia in mice with hypoxia-induced pulmonary hypertension and strengthens the previous finding that p27 is the only CDKI involved in heparin regulation of PASMC proliferation and hypoxia-induced pulmonary hypertension.
Yu
Lunyin
L
Department of Medicine, Pulmonary and Critical Care Unit, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, USA.
Quinn
Deborah A
DA
Garg
Hari G
HG
Hales
Charles A
CA
D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics; D002478:Cells, Cultured; D056742:Cyclin D2; D051357:Cyclin-Dependent Kinase 2 / Q000235:genetics; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics*; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics; D016213:Cyclins / Q000235:genetics; D050704:E2F4 Transcription Factor / Q000235:genetics; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D006493:Heparin / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000503:physiopathology; D000860:Hypoxia / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics; D011725:Pyridines / Q000494:pharmacology; D050720:Retinoblastoma-Like Protein p107 / Q000235:genetics; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics
C486196:Ccnd2 protein, mouse; C503689:Ccne2 protein, mouse; D018797:Cell Cycle Proteins; D056742:Cyclin D2; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D050763:Cyclin-Dependent Kinase Inhibitor p18; D016213:Cyclins; D050704:E2F4 Transcription Factor; C493763:E2f4 protein, mouse; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; C489485:Rbl1 protein, mouse; D050720:Retinoblastoma-Like Protein p107; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006493:Heparin; D051357:Cyclin-Dependent Kinase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one