title: SMAD proteins are involved in apoptosis induction in ventricular cardiomyocytes.
abstract: OBJECTIVE
  The transcription factor AP-1 is a mediator of hypertrophic growth and apoptosis in cardiomyocytes. This puts AP-1 in the center of two important processes found in the failing heart and implies that variations (i) in the AP-1 composition itself or (ii) in additional, interacting transcription factors are responsible for the diverse actions of AP-1. To test this hypothesis, we performed studies on isolated ventricular cardiomyocytes of rat under hypertrophy- or apoptosis-inducing conditions.
  
  
  RESULTS
  The NO donor SNAP (100 microM), which is a pro-apoptotic stimulus in cardiomyocytes, activated AP-1 within 2 h. c-Jun, JunB and FosB are identified as the main components of this AP-1 complex. This complex formation is identical to the composition of AP-1 found under hypertrophic growth stimulation by phenylephrine (PE, 10 muM). Analysis of other transcription factors able to interact with AP-1 revealed activation of SMAD activity only during stimulation with SNAP to 131+/-9.6% (p < 0.05 vs. control, n = 9). The SMAD complex is formed from SMAD4 and 3. Intracellular scavenging of SMAD proteins by transformation of cardiomyocytes with SMAD decoy oligonucleotides or inhibition of SMAD4 synthesis using SMAD4 antisense oligonucleotides reduced the number of apoptotic cells under stimulation with SNAP from 13.3 +/- 1.2% to control levels (8 +/- 1%, p < 0.05, n = 6). TGFbeta, which is a known stimulator of SMAD proteins, is also shown to stimulate apoptosis in cardiomyocytes. Again, simultaneous activation of AP-1 and SMAD is needed for this apoptosis induction.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Physiology, Justus-Liebig-University, Aulweg 129 D-35392, Giessen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Schneiders
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Heger
authors.forename: Patrick
authors.initials: P
authors.lastname: Best
authors.forename: Hans
authors.initials: H
authors.lastname: Michael Piper
authors.forename: Gerhild
authors.initials: G
authors.lastname: Taimor
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D017208:Rats, Wistar; D013268:Stimulation, Chemical; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000316:Adrenergic alpha-Agonists; D020030:Nitric Oxide Donors; C110881:S-nitro-N-acetylpenicillamine; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D010656:Phenylephrine; D010396:Penicillamine