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., ␣-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...

Sympathetic outflow activates the venom gland of the snakeBothrops jararacaby regulating the activation of transcription factors and the synthesis of venom gland proteins

“…Our finding that the stimulation of α 1 -and β-adrenoceptors causes activation of NFκB and AP-1 in the venom gland is in line with several studies that show that the stimulation of α-and β-adrenoceptors induces c-fos expression in a variety of cells, including cardiac myocytes, vascular smooth muscle cells, neuroblastoma cells, brown adipocytes and hepatocytes (Iwaki et al, 1990;Shilling et al, 1991;Okazaki et al, 1994;Thonberg et al, 1994;GarciaSáinz and Alcántara-Hernández, 1996;Im et al, 1998;Taimor et al, 2004). All α-adrenoceptor subtypes were able to induce the expression of c-fos and c-jun, and this effect seems to be mediated by PKC, but α 1 -adrenoceptor subtypes vary in the efficacy of this induction (García-Saínz et al, 1998).…”

Fibronectin Increases Matrix Metalloproteinase 9 Expression through Activation of c-Fos via Extracellular-regulated Kinase and Phosphatidylinositol 3-Kinase Pathways in Human Lung Carcinoma Cells

“…CRE- decoy oligonucleotides may provide a powerful new means of combating cancers, and other pathological conditions by regulating the expression of cAMP-responsive genes (25). Phenylephrine stimulated DNA binding activity of AP-1 and increased protein synthesis in cardiomyocytes of adult rats, and inhibition of AP-1 binding activity by CRE-decoy oligonucleotides abolished both of these growth responses (57). In another study, the CRE-decoy oligonucleotide treatment was shown to inhibit ovarian cancer cell growth and caused a marked reduction in MMP-9 activity (58).…”

Down-Regulation of Calpain 9 is Linked to Hypertensive Heart and Kidney

“…E.g., NFAT3, MEF-2 and GATA-4 have been reported to play a role in cardiac hypertrophy [18,19]. Moreover, fos and jun, known substrates of calpain 1 and 2 [20], can act as causal mediators of hypertrophic growth of cardiomyocytes [21,22]. The search of substrates for calpain 9, especially in heart and kidney as target organs, may be a key activity in order to understand the mode of action of this calpain isoform in cardiovascular diseases.…”