BACKGROUND: Left ventricular (LV) remodeling after myocardial infarction is associated with hypertrophy of surviving myocytes and represents a major process that leads to heart failure. One of the intrinsic histone acetyltransferases, p300, serves as a coactivator of hypertrophy-responsive transcriptional factors such as a cardiac zinc finger protein GATA-4 and is involved in its hypertrophic stimulus-induced acetylation and DNA binding. However, the role of p300-histone acetyltransferase activity in LV remodeling after myocardial infarction in vivo is unknown. METHODS AND RESULTS: To solve this problem, we have generated transgenic mice overexpressing intact p300 or mutant p300 in the heart. As the result of its 2-amino acid substitution in the p300-histone acetyltransferase domain, this mutant lost its histone acetyltransferase activity and was unable to activate GATA-4-dependent transcription. The two kinds of transgenic mice and the wild-type mice were subjected to myocardial infarction or sham operation at the age of 12 weeks. Intact p300 transgenic mice showed significantly more progressive LV dilation and diminished systolic function after myocardial infarction than wild-type mice, whereas mutant p300 transgenic mice did not show this. CONCLUSIONS: These findings demonstrate that cardiac overexpression of p300 promotes LV remodeling after myocardial infarction in adult mice in vivo and that histone acetyltransferase activity of p300 is required for these processes.
BACKGROUND: Left ventricular (LV) remodeling after myocardial infarction is associated with hypertrophy of surviving myocytes and represents a major process that leads to heart failure. One of the intrinsic histone acetyltransferases, p300, serves as a coactivator of hypertrophy-responsive transcriptional factors such as a cardiac zinc finger protein GATA-4 and is involved in its hypertrophic stimulus-induced acetylation and DNA binding. However, the role of p300-histone acetyltransferase activity in LV remodeling after myocardial infarction in vivo is unknown. METHODS AND RESULTS: To solve this problem, we have generated transgenic mice overexpressing intact p300 or mutant p300 in the heart. As the result of its 2-amino acid substitution in the p300-histone acetyltransferase domain, this mutant lost its histone acetyltransferase activity and was unable to activate GATA-4-dependent transcription. The two kinds of transgenic mice and the wild-type mice were subjected to myocardial infarction or sham operation at the age of 12 weeks. Intact p300transgenic mice showed significantly more progressive LV dilation and diminished systolic function after myocardial infarction than wild-type mice, whereas mutant p300transgenic mice did not show this. CONCLUSIONS: These findings demonstrate that cardiac overexpression of p300 promotes LV remodeling after myocardial infarction in adult mice in vivo and that histone acetyltransferase activity of p300 is required for these processes.
Authors: Domenick A Prosdocimo; Priti Anand; Xudong Liao; Han Zhu; Shamanthika Shelkay; Pedro Artero-Calderon; Lilei Zhang; Jacob Kirsh; D'Vesharronne Moore; Mariana G Rosca; Edwin Vazquez; Janos Kerner; Kemal M Akat; Zev Williams; Jihe Zhao; Hisashi Fujioka; Thomas Tuschl; Xiaodong Bai; P Christian Schulze; Charles L Hoppel; Mukesh K Jain; Saptarsi M Haldar Journal: J Biol Chem Date: 2014-01-08 Impact factor: 5.157
Authors: Djordje Djordjevic; Vinita Deshpande; Tomasz Szczesnik; Andrian Yang; David T Humphreys; Eleni Giannoulatou; Joshua W K Ho Journal: Biophys Rev Date: 2014-12-10
Authors: Roberto Papait; Paola Cattaneo; Paolo Kunderfranco; Carolina Greco; Pierluigi Carullo; Alessandro Guffanti; Valentina Viganò; Giuliano Giuseppe Stirparo; Michael V G Latronico; Gerd Hasenfuss; Ju Chen; Gianluigi Condorelli Journal: Proc Natl Acad Sci U S A Date: 2013-11-27 Impact factor: 11.205