In conclusion, AP-1/SMAD signaling has been identified as a common pathway in cardiomyocyte apoptosis. In contrast, SMAD proteins are dispensable for AP-1-mediated hypertrophic growth. This finding characterizes SMAD proteins as potential candidates for proteins that shift AP-1 signaling from hypertrophy to apoptosis.

.-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., ␣-and ␤-adrenoceptor agonists [10 M phenylephrine (PE) and 1 M isoprenaline (Iso), respectively]. After 1 h of stimulation with PE, mRNA expression of c-Fos and c-Jun was upregulated to 185 Ϯ 32 and 132 Ϯ 13% of control. Fos and Jun proteins formed the AP-1 complex. PE stimulated DNA binding activity of AP-1 to 165 Ϯ 22% of control within 2 h and increased protein synthesis to 161 Ϯ 27% of control and cross-sectional area to 126 Ϯ 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 Ϯ 19% of control within 2 h and stimulated protein synthesis to 145 Ϯ 17% of control. However, the growth effect of Iso was not abolished by CRE decoys: Iso increased protein synthesis to 158 Ϯ 17% of control in the presence of CRE. In conclusion, AP-1 is a causal mediator of the ␣-adrenergic, but not the ␤-adrenergic, growth response of cardiomyocytes.hypertrophy; adrenoceptors; immediate early genes; transcription factors HYPERTROPHIC GROWTH of the heart is accompanied by an increase in the expression of Fos and Jun family members. This has been documented in several models of cardiac hypertrophy: in hearts after pressure overload in vivo (2, 18) and in isolated hearts or cardiomyocytes after adrenergic stimulation (1, 5). Jun and Fos family members can dimerize to form the transcription factor activator protein 1 (AP-1) (7). Correlations between formation of AP-1 and hypertrophic growth have also been shown in several experimental models, e.g., in hearts of stroke-prone spontaneously hypertensive rats and in hearts of rats infused with angiotensin II or isoprenaline (Iso) (6, 27, 24), as well as in phenylephrine (PE)-or endothelin-stimulated neonatal cardiomyocytes (12). These studies have suggested a causal role of AP-1 in cardiac hypertrophy. However, this seems not to be generally true. In neonatal cardiomyocytes, expression of Fos and Jun family members can be upregulated by ATP without promoting myocyte hypertrophy (28). In adult cardiomyocytes, we previously identified AP-1 as a mediator of nitric oxide-induced apoptotic cell death (25). Additionally, the transcription of atrial natriuretic factor, a marker gene for hypertrophic growth that contains an AP-1 binding site in its promoter, can be stimulated by overexpression of Jun but is decreased by overexpression of Fos (10). These examples show that there are exceptions from the correlation of AP-1 formation with cardiac hypertrophy.It is unclear whether these differences in the role of AP-1 in car...