Transcription activator protein 1 mediates α- but not β-adrenergic hypertrophic growth responses in adult cardiomyocytes

Abstract

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., α- and β-adrenoceptor agonists [10 μM phenylephrine (PE) and 1 μM 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 α-adrenergic, but not the β-adrenergic, growth response of cardiomyocytes.