Conditional Cardiac Overexpression of S100A6 Attenuates Myocyte Hypertrophy and Apoptosis Following Myocardial Infarction

Author(s): James T. Tsoporis, Shehla Izhar, Jean-Francois Desjardins, Howard Leong-Poi, Thomas G. Parker

Journal Name: Current Pharmaceutical Design

Volume 20 , Issue 12 , 2014

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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.

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Article Details

VOLUME: 20
ISSUE: 12
Year: 2014
Page: [1941 - 1949]
Pages: 9
DOI: 10.2174/13816128113199990444
Price: $65

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