The Molecular Basis of Cardiac Senescence: From Transcriptomics to Function

心血管科学实验室一直致力于老化心肌的研究。最近，我们开始研究心脏的基因表达谱，以解释哺乳动物普遍存在的寿命差异。寿命变异性是哺乳动物衰老的一个共同特征，但造成这种变异性的机制在很大程度上仍然未知。利用微阵列数据集和微阵列预测分析（PAM），我们在Wistar和Fisher 344大鼠中发现了一组具有不同表达谱的心脏转录本，可以预测相对寿命。来自第三个36个月大的Fisher x Norway Brown （F/N）的大鼠心脏转录组的PAM测试验证了这一相对寿命基因子集的预测价值。这个信息性基因集的表达模式是高度保守的，并被用来鉴定与这种表达模式有关的常见顺式元件和反式激活因子。具体来说，心脏中存在的四个转录因子（Max、Ets2、Erg和Msx2）的丰度表现出与寿命相关的、菌株无关的变化，但只有Ets2具有与相对寿命基因集直接相关的表达谱。ETS2在CMs中普遍存在，在死亡率呈指数增长之前，主要在成年大鼠心脏中表现出高度的心肌细胞间变异性。在这个时间点，心肌细胞中升高的ETS2与TUNEL染色重叠，并且在交感刺激下上调。在功能上，腺病毒介导的ETS2过表达促进了CMs中aif介导的、不依赖caspase的程序性坏死，这种坏死可以被PARP-1抑制剂DPQ完全抑制。我们得出结论，成年啮齿动物心脏中ETS2丰度的变化和相关的CMs损失，至少在一定程度上促成了在哺乳动物正常衰老过程中通过激活程序性坏死观察到的寿命变异性。这项工作现已提交出版。

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.