Gene program for cardiac cell survival induced by transient ischemia in conscious pigs
Gene program for cardiac cell survival induced by transient ischemia in conscious pigs
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DOI：
10.1073/pnas.171297498
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发表时间：
2001-07-31
影响因子：
11.1
通讯作者：
Vatner, SF
中科院分区：
文献类型：
--
作者：
Depre, C;Tomlinson, JE;Vatner, SF
缺血性心脏病的治疗传统上是以限制细胞坏死为目的。我们通过基因组图谱确定缺血心肌是否可以触发促进心肌细胞存活的遗传程序，这将是一种新的、潜在的同等重要的挽救机制。虽然心脏基因组学通常在啮齿类动物身上进行，但我们使用的是猪的缺血/再灌注模型，随后是心功能不全(眩晕)，这更接近临床情况。用消减杂交法比较同一心脏缺血组织和正常组织的基因表达谱。在缺血心肌中上调的核编码基因中，约有三分之一(23/74)参与了存活机制(抑制细胞凋亡、细胞保护、细胞生长和刺激翻译)。Northern印迹和定量聚合酶链式反应证实了该反应的特异性。出乎意料的是，这个程序还包括了以前没有描述过的虹膜心肌细胞的基因。存活基因的上调在心内膜下比心外膜下更明显，反映了这种反应在顿抑心肌中与缺血损伤的严重程度成正比。因此，在一个概括人类心脏病的猪模型中，非致命性缺血激活了与心肌顿抑时间进程相关的细胞存活基因组程序，并与导致心肌顿抑的缺血应激存在跨壁差异。了解在心肌顿抑过程中上调的基因，包括那些以前在心脏中没有描述的基因，并开发激活这一程序的策略，可能会为缺血性心脏病的治疗开辟新的途径。
Therapy for ischemic heart disease has been directed traditionally at limiting cell necrosis. We determined by genome profiling whether ischemic myocardium can trigger a genetic program promoting cardiac cell survival which would be a novel and potentially equally important mechanism of salvage. Although cardiac genomics is usually performed in rodents, we used a swine model of ischemia/reperfusion followed by ventricular dysfunction (stunning), which more closely resembles clinical conditions. Gene expression profiles were compared by subtractive hybridization between ischemic and normal tissue of the same hearts. About one-third (23/74) of the nuclear-encoded genes that were upregulated in ischemic myocardium participate in survival mechanisms (inhibition of apoptosis, cytoprotection, cell growth, and stimulation of translation). The specificity of this response was confirmed by Northern blot and quantitative PCR. Unexpectedly, this program also included genes not previously described iri cardiomyocytes. Up-regulation of survival genes was more profound in subendocardium over subepicardium, reflecting that this response in stunned myocardium was proportional to the severity of the ischemic insult. Thus, in a swine model that recapitulates human heart disease, nonlethal ischemia activates a genomic program of cell survival that relates to the time course of myocardial stunning and differs transmurally in relation to ischemic stress, which induced the stunning. Understanding the genes up-regulated during myocardial stunning, including those not previously described in the heart, and developing strategies that activate this program may open new avenues for therapy in ischemic heart disease.