The Molecular Basis of Cardiac Senescence: From Transcriptomics to Function

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The Laboratory of Cardiovascular Science has a strong commitment to the study of aging myocardium. Most recently, we have begun to look at gene expression profiles in heart to explain the variability in lifespan common to mammals. Longevity variability is a common feature of aging in mammals, but the mechanisms responsible for this variability remain largely unknown. Using microarray datasets coupled with Prediction analysis of microarrays (PAM), we identified a set of cardiac transcripts with distinct expression profiles predictive of relative lifespan in Wistar and Fisher 344 rats. PAM tests of rat heart transcriptomes from a third longer lived 36-month-old Fisher x Norway Brown (F/N) validated the predictive value of this relative lifespan gene subset. The expression patterns of this informative gene set were highly conserved and employed to identify common ciselements and trans-activating factors implicated in this expression pattern. 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. ETS2 was prevalent in 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. Elevated ETS2 overlapped with TUNEL staining in heart myocytes at this time point, and it is up-regulated in response to sympathetic stimuli. Functionally, adenovirus mediated over-expression of ETS2 promotes AIF-mediated, caspase-independent programmed necrosis 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 mammals through activation of programmed necrosis. This work has now been submitted for publication.