title: Increase in cardiac M2-muscarinic receptor expression is regulated by GATA binding protein 4 (GATA-4) in streptozotocin-induced diabetic rats.
abstract: BACKGROUND
  An increase in cardiac M2-muscarinic receptor (M2-mAChR) expression in diabetic rats has been observed, but the molecular mechanism of this increase remains unclear. The transcriptional activity of GATA binding protein 4 (GATA-4) has been documented to regulate the expression of M2-mAChR genes. In this study, we were interested in identifying the role of GATA-4 in the increase in M2-mAChR in diabetic rats and a primary culture of cardiomyocytes.
  
  
  METHODS
  Streptozotocin-induced diabetic rats (STZ-rats) and high-glucose (D-glucose 30 mM, 24h)-treated primary cultures of cardiomyocytes from neonatal rats were used to investigate the role of GATA-4 in the change in M2-mAChR. The protein expression was determined by Western blot analysis. Phlorizin (Na(+)-glucose co-transport inhibitor), insulin, tiron (radical scavenger), PD98059 (ERK inhibitor) and SB203580 (p38 inhibitor) were used. We also silenced GATA-4 by RNAi to investigate the changes in M2-mAChR expression.
  
  
  RESULTS
  The cardiac output was reduced in STZ-rats with a higher expression of M2-mAChR or phosphorylated GATA-4 in the heart. These changes were reversed after correction of the blood sugar level. In cardiomyocytes, high glucose treatment also increased M2-mAChR expression and GATA-4 phosphorylation. These changes were reversed by tiron (ROS scavenger) or PD98059 (MEK/ERK inhibitor). However, an increase in M2-mAChR expression was not observed when GATA-4 was silenced by small interfering RNA (siRNA) in cardiomyocytes.
  
  
  CONCLUSIONS
  We suggest that hyperglycemia can cause a higher expression of M2-mAChR in cardiomyocytes mainly through ROS to enhance MEK/ERK for phosphorylation of GATA-4.
authors.affiliation: Department of Cardiology, Kaohsiung Veterans General Hospital, Kaohsiung City 81301, Taiwan.
authors.forename: Guang-Yuan
authors.initials: GY
authors.lastname: Mar
authors.forename: Po-Ming
authors.initials: PM
authors.lastname: Ku
authors.forename: Li-Jen
authors.initials: LJ
authors.lastname: Chen
authors.forename: Kai-Chun
authors.initials: KC
authors.lastname: Cheng
authors.forename: Yin-Xiao
authors.initials: YX
authors.lastname: Li
authors.forename: Juei-Tang
authors.initials: JT
authors.lastname: Cheng
mesh_terms: D000818:Animals; D002302:Cardiac Output / Q000502:physiology; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D050991:GATA4 Transcription Factor / Q000502:physiology*; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology; D008297:Male; D032383:Myocytes, Cardiac / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D043585:Receptor, Muscarinic M2 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D050991:GATA4 Transcription Factor; D043585:Receptor, Muscarinic M2