Abstract
S100A6, a 20 kDa, Ca2+ - binding dimer with low basal cardiac expression, is upregulated in the rat heart following infarction and forced expression of S100A6 in rat neonatal cardiac myocyte cultures, inhibited the induction of β myosin heavy chain (MHC), skeletal α actin (skACT) and myocyte apoptosis in response to diverse stimuli including tumor necrosis factor α. To define a role for S100A6 in vivo, we generated cardiac myocyte-specific transgenic mice by placing the human S100A6 cDNA downstream of a promoter responsive to a doxycycline (DOX)-regulated transcriptional activator (tTA) and breeding this line with one harboring cardiac myocyterestricted (αMHC) expression of tTA (αMHC-tTA). We compared S100A6-αMHC-tTA mice 35 days post-myocardial infarction (MI) produced by coronary artery ligation with similar matched sham-operated controls on (S100A6 transgene overexpressed) or off (S100A6 transgene silenced) DOX. There were no differences between the sham groups on or off DOX. Thirty five days post-MI, myocardial S100A6 levels increased 12.5-fold in S100A6-α-MHC-tTA mice off DOX compared with S100A6-α-MHC-tTA mice on DOX. Hemodynamic studies, echocardiography and postmortem examination indicated that S100A6-αMHC-tTA mice on DOX 35 days post-MI mounted a hypertrophic response (20-22.5 % increase) accompanied by a program of fetal gene re-expression, fibrosis and myocardial apoptosis. Whereas the S100A6-α-MHC-tTA mice off DOX showed an attenuated myocyte hypertrophic response, less fibrosis and apoptosis which was beneficial to preservation of cardiac function. Therefore, S100A6 is a potential therapeutic target for modulation of adverse left ventricular remodeling in the early post infarct period.
Keywords: Hypertrophy, S100A6, calcium binding proteins, transgenic, apoptosis, myocardial infarction.
Current Pharmaceutical Design
Title:Conditional Cardiac Overexpression of S100A6 Attenuates Myocyte Hypertrophy and Apoptosis Following Myocardial Infarction
Volume: 20 Issue: 12
Author(s): James T. Tsoporis, Shehla Izhar, Jean-Francois Desjardins, Howard Leong-Poi and Thomas G. Parker
Affiliation:
Keywords: Hypertrophy, S100A6, calcium binding proteins, transgenic, apoptosis, myocardial infarction.
Abstract: S100A6, a 20 kDa, Ca2+ - binding dimer with low basal cardiac expression, is upregulated in the rat heart following infarction and forced expression of S100A6 in rat neonatal cardiac myocyte cultures, inhibited the induction of β myosin heavy chain (MHC), skeletal α actin (skACT) and myocyte apoptosis in response to diverse stimuli including tumor necrosis factor α. To define a role for S100A6 in vivo, we generated cardiac myocyte-specific transgenic mice by placing the human S100A6 cDNA downstream of a promoter responsive to a doxycycline (DOX)-regulated transcriptional activator (tTA) and breeding this line with one harboring cardiac myocyterestricted (αMHC) expression of tTA (αMHC-tTA). We compared S100A6-αMHC-tTA mice 35 days post-myocardial infarction (MI) produced by coronary artery ligation with similar matched sham-operated controls on (S100A6 transgene overexpressed) or off (S100A6 transgene silenced) DOX. There were no differences between the sham groups on or off DOX. Thirty five days post-MI, myocardial S100A6 levels increased 12.5-fold in S100A6-α-MHC-tTA mice off DOX compared with S100A6-α-MHC-tTA mice on DOX. Hemodynamic studies, echocardiography and postmortem examination indicated that S100A6-αMHC-tTA mice on DOX 35 days post-MI mounted a hypertrophic response (20-22.5 % increase) accompanied by a program of fetal gene re-expression, fibrosis and myocardial apoptosis. Whereas the S100A6-α-MHC-tTA mice off DOX showed an attenuated myocyte hypertrophic response, less fibrosis and apoptosis which was beneficial to preservation of cardiac function. Therefore, S100A6 is a potential therapeutic target for modulation of adverse left ventricular remodeling in the early post infarct period.
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Cite this article as:
Tsoporis T. James, Izhar Shehla, Desjardins Jean-Francois, Leong-Poi Howard and Parker G. Thomas, Conditional Cardiac Overexpression of S100A6 Attenuates Myocyte Hypertrophy and Apoptosis Following Myocardial Infarction, Current Pharmaceutical Design 2014; 20 (12) . https://dx.doi.org/10.2174/13816128113199990444
DOI https://dx.doi.org/10.2174/13816128113199990444 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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