Transcription activator protein 1 mediates alpha- but not beta-adrenergic hypertrophic growth responses in adult cardiomyocytes.
In some models of cardiac hypertrophy, activation of activator protein 1 (AP-1) correlates with growth. However, AP-1 is also activated by stimuli not involved in cardiac growth. This raises the following questions: does AP-1 plays a causal role for cardiomyocyte growth, and is this role model or stimulus dependent? We used a single model to address these questions, i.e., ventricular cardiomyocytes of adult rats, and two growth stimuli, i.e., alpha- and beta-adrenoceptor agonists [10 microM phenylephrine (PE) and 1 microM isoprenaline (Iso), respectively]. After 1 h of stimulation with PE, mRNA expression of c-Fos and c-Jun was upregulated to 185 +/- 32 and 132 +/- 13% of control. Fos and Jun proteins formed the AP-1 complex. PE stimulated DNA binding activity of AP-1 to 165 +/- 22% of control within 2 h and increased protein synthesis to 161 +/- 27% of control and cross-sectional area to 126 +/- 4% of control. Inhibition of AP-1 binding activity by cAMP response element (CRE) decoy oligonucleotides abolished both of these growth responses. Iso stimulated AP-1 binding activity to 203 +/- 19% of control within 2 h and stimulated protein synthesis to 145 +/- 17% of control. However, the growth effect of Iso was not abolished by CRE decoys: Iso increased protein synthesis to 158 +/- 17% of control in the presence of CRE. In conclusion, AP-1 is a causal mediator of the alpha-adrenergic, but not the beta-adrenergic, growth response of cardiomyocytes.
Taimor
G
G
Physiologisches Institut, Justus-Liebig-Universität, Aulweg 129, 35392 Giessen, Germany. Gerhild.Taimor@physiologie.med.uni-giessen.de
Schlüter
K-D
KD
Best
P
P
Helmig
S
S
Piper
H M
HM
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D017781:Genes, Immediate-Early / Q000502:physiology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D011942:Receptors, Adrenergic, alpha / Q000235:genetics*; D011943:Receptors, Adrenergic, beta / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000378:metabolism*
D000316:Adrenergic alpha-Agonists; D000318:Adrenergic beta-Agonists; D012333:RNA, Messenger; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D018808:Transcription Factor AP-1; D010656:Phenylephrine; D007545:Isoproterenol