Inositol polyphosphate 1-phosphatase is a novel antihypertrophic factor.
Activation of G(q)-coupled alpha(1)-adrenergic receptors leads to hypertrophic growth of neonatal rat ventricular cardiomyocytes that is associated with increased expression of hypertrophy-related genes, including atrial natriuretic peptide (ANP) and myosin light chain-2 (MLC), as well as increased ribosome synthesis. The role of inositol phosphates in signaling pathways involved in these changes in gene expression was examined by overexpressing inositol phosphate-metabolizing enzymes and determining effects on ANP, MLC, and 45 S ribosomal gene expression following co-transfection of appropriate reporter gene constructs. Overexpression of enzymes that metabolize inositol 1,4,5-trisphosphate did not reduce ANP or MLC responses, but overexpression of the enzyme primarily responsible for metabolism of inositol 4,5-bisphosphate (Ins(1,4)P(2)), inositol polyphosphate 1-phosphatase (INPP), reduced ANP and MLC responses associated with alpha(1)-adrenergic receptor-mediated hypertrophy. Similarly overexpressed INPP reduced ANP and MLC responses associated with contraction-induced hypertrophy. In addition, overexpression of INPP reduced the increase in ribosomal DNA transcription associated with both hypertrophic models. Hypertrophied cells from both cell models as well as ventricular tissue from mouse hearts hypertrophied by pressure overload in vivo contained heightened levels of Ins(1,4)P(2), suggesting reduced INPP activity in three different models of hypertrophy. These studies provide evidence for an involvement of Ins(1,4)P(2) in hypertrophic signaling pathways in ventricular myocytes.
Woodcock
Elizabeth A
EA
Cellular Biochemistry Laboratory, Baker Medical Research Institute, PO Box 6492, St. Kilda Road Central, Melbourne, 8008, Victoria, Australia. liz.woodcock@baker.edu.au
Wang
Bing Hui
BH
Arthur
Jane F
JF
Lennard
Alicia
A
Matkovich
Scot J
SJ
Du
Xiao-Jun
XJ
Brown
Joan Heller
JH
Hannan
Ross D
RD
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D015153:Blotting, Western; D016466:CHO Cells; D024722:Cardiac Myosins / Q000378:metabolism; D002478:Cells, Cultured; D003001:Cloning, Molecular; D006224:Cricetinae; D018076:DNA, Complementary / Q000378:metabolism; D004275:DNA, Ribosomal / Q000378:metabolism; D004591:Electrophoresis, Polyacrylamide Gel; D015723:Gene Library; D017930:Genes, Reporter; D006801:Humans; D006984:Hypertrophy / Q000188:drug therapy*; D007295:Inositol Phosphates / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008956:Models, Chemical; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D018994:Myosin Light Chains / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry* / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
D018076:DNA, Complementary; D004275:DNA, Ribosomal; D007295:Inositol Phosphates; D018994:Myosin Light Chains; C107184:myosin light chain 2; D009320:Atrial Natriuretic Factor; C066454:inositol 4,5-bisphosphate; D011493:Protein Kinase C; D010744:Phosphoric Monoester Hydrolases; C053087:inositol-1,4-bisphosphate 1-phosphatase; D024722:Cardiac Myosins