TY - JOUR
T1 - Linkage of cardiac gene expression profiles and ETS2 with lifespan variability in rats
AU - Sheydina, Anna
AU - Volkova, Maria
AU - Jiang, Liqun
AU - Juhasz, Ondrej
AU - Zhang, Jing
AU - Tae, Hyun Jin
AU - Perino, Maria G.
AU - Wang, Mingyi
AU - Zhu, Yi
AU - Lakatta, Edward G.
AU - Boheler, Kenneth R.
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2012/4
Y1 - 2012/4
N2 - Longevity variability is a common feature of aging in mammals, but the mechanisms responsible for this remain largely unknown. Using microarray datasets coupled with prediction analysis of microarrays (PAM), we identified a set of 252 cardiac transcripts predictive of relative lifespan in Wistar and Fisher 344 rats. Prediction analysis of microarrays 'tests' of rat heart transcriptomes from a third longer lived Fisher×Norway Brown rat strain validated the predictive value of this gene subset. The expression patterns of these genes were highly conserved, and corresponding promoter regions were employed to identify common cis-elements and trans-activating factors implicated in their control. Specifically, four transcription factors (Max, Ets2, Erg, and Msx2) present in heart displayed longevity-dependent, strain-independent changes in abundance, but only ETS2 had an expression profile that directly correlated with the relative lifespan gene set. In heart, ETS2 was prevalent in cardiomyocytes (CMs) and showed a high degree of myocyte-to-myocyte variability predominantly in adult rat hearts prior to the exponential increase in the rate of mortality. Exclusively in this group, elevated ETS2 significantly overlapped with TUNEL staining in heart myocytes. In response to sympathetic stimuli, ETS2 is also up-regulated, and functionally, adenovirus-mediated over-expression of ETS2 promotes apoptosis-inducing factor-mediated, caspase-independent programmed necrosis exclusively in CMs that can be fully inhibited by the PARP-1 inhibitor DPQ. We conclude that variations in ETS2 abundance in hearts of adult rodents and the associated loss of CMs contribute at least partially, to the longevity variability observed during normal aging of rats through activation of programmed necrosis.
AB - Longevity variability is a common feature of aging in mammals, but the mechanisms responsible for this remain largely unknown. Using microarray datasets coupled with prediction analysis of microarrays (PAM), we identified a set of 252 cardiac transcripts predictive of relative lifespan in Wistar and Fisher 344 rats. Prediction analysis of microarrays 'tests' of rat heart transcriptomes from a third longer lived Fisher×Norway Brown rat strain validated the predictive value of this gene subset. The expression patterns of these genes were highly conserved, and corresponding promoter regions were employed to identify common cis-elements and trans-activating factors implicated in their control. Specifically, four transcription factors (Max, Ets2, Erg, and Msx2) present in heart displayed longevity-dependent, strain-independent changes in abundance, but only ETS2 had an expression profile that directly correlated with the relative lifespan gene set. In heart, ETS2 was prevalent in cardiomyocytes (CMs) and showed a high degree of myocyte-to-myocyte variability predominantly in adult rat hearts prior to the exponential increase in the rate of mortality. Exclusively in this group, elevated ETS2 significantly overlapped with TUNEL staining in heart myocytes. In response to sympathetic stimuli, ETS2 is also up-regulated, and functionally, adenovirus-mediated over-expression of ETS2 promotes apoptosis-inducing factor-mediated, caspase-independent programmed necrosis exclusively in CMs that can be fully inhibited by the PARP-1 inhibitor DPQ. We conclude that variations in ETS2 abundance in hearts of adult rodents and the associated loss of CMs contribute at least partially, to the longevity variability observed during normal aging of rats through activation of programmed necrosis.
KW - Aging
KW - Microarrays
KW - Mortality
KW - Prediction analysis of microarrays
KW - Rat
KW - Transcription factors
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U2 - 10.1111/j.1474-9726.2012.00794.x
DO - 10.1111/j.1474-9726.2012.00794.x
M3 - Article
C2 - 22247964
AN - SCOPUS:84862800671
VL - 11
SP - 350
EP - 359
JO - Aging Cell
JF - Aging Cell
SN - 1474-9718
IS - 2
ER -