Global expression profiling of hypertrophy-associated genes regulated by a transcriptional coactivator, p300

Global expression profiling of hypertrophy-associated genes regulated by a transcriptional coactivator, p300

Teruhisa Kawamura1, Koh Ono1, Tomohide Takaya1, Shoichi Miyamoto2, Tatsuya Morimoto2, Yosuke Kawase3, Toru Kita2, Koji Hasegawa1.

  1. Division of Translational Research, Kyoto Medical Center, National Hospital Organization, Kyoto, Japan.
  2. Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
  3. Chugai Research Institute for Medical Science, Inc., Shizuoka, Japan.

第70回日本循環器学会学術集会 (名古屋), 2006/03/25 (ポスター).

Abstract

An intrinsic histone acetyltransferase p300 serves as a coactivator of hypertrophy-responsive transcriptional factors such as MEF-2 and GATA-4. Analysis of transgenic mice (Tg) with cardiac-specific overexpression of p300 revealed that p300-mediated nuclear acetylation is involved in pathological myocyte growth with decompensated heart failure. To elucidate pathways for heart failure, we performed genechip analysis and analyzed global gene expression profiles in the hearts of p300-Tg. We previously reported that p300-Tg hearts developed severe decompensated heart failure at the age of 24 weeks. However, at the age of 10 weeks, echocardiography demonstrated that left ventricular systolic and diastolic dimensions were similar between p300-Tg and wild-type mice (WT). At this pre-heart failure stage, RNA isolated from these mouse hearts was subjected to transcriptome analysis by oligonucleotide array hybridization. We found that even in this stage, cardiac expression of β-myosin heavy chain gene, is much higher (about 8-fold) in Tg than WT. Interestingly, one of tyrosine kinase receptors, platelet derived growth factor receptor α (PDGFRα) was highly expressed in Tg hearts compared with WT hearts. In primary cardiac myocytes from neonatal rats, administration of anti-PDGFRα neutralizing antibody almost completely inhibited phenylephrine-induced hypertrophic responses such as myofiber organization and increase in cell size. Thus, PDGFRα, one of p300 downstreatm target genes, might represent a pathway for heart failure.