Myocardial gene expression of hibernating and control tissue from patients with ischemic left ventricular dysfunction

Objectives: While cardiac scar tissue is damaged irreversibly, hibernating myocardium is characterized by reversible contractile dysfunction. Limited data are available in humans regarding the molecular biology of hibernating myocardium. The aim of this study was to identify new molecular mechanisms distinctive for human hibernating myocardium by gene expression analysis. Results: Of 4,171 transcripts examined, we identified 86 to be differentially expressed. Twentyone genes showed an increased and 65 genes a decreased expression in hibernating myocardium. Functional clustering revealed major changes in the expression of genes associated with transcription, protein modification and phosphorylation, regulation of apoptosis and intercellular communication. Besides the reported upregulation of ß-adrenergic receptor kinase-1 in heart failure, we observed new gene expression patterns, such as the upregulation of fas-activated serine/threonine kinase (FAST) or reduced expression of desmoplakin. Downregulation of desmoplakin in cardiomyocytes from hibernating myocardium was also seen on the protein level, consistent with a role of this protein in the development of a dilative cardiomyopathy. Conclusions: Gene expression analysis of hibernating myocardium provided novel insights into the molecular mechanisms underlying ischemic heart failure. Dysfunction of desmosomes may contribute to impaired contractility and dilative tissue remodeling. Keywords: disease state analysis Methods: We compared in patients with advanced coronary artery disease and impaired left ventricular function the gene expression profile of myocardial biopsies from hibernating myocardium (n=5), as identified in PET by a mismatch between perfusion and glucose metabolism, with expression profiles of matched biopsies from remote myocardium. Gene-specific PCR of selected genes was used to validate our technical approach. Immunohistochemical staining was performed for one gene of specific interest.

目标：尽管心脏瘢痕组织为不可逆损伤，冬眠心肌（hibernating myocardium）以可逆性收缩功能障碍为特征。目前关于人类冬眠心肌的分子生物学研究数据较为有限。本研究旨在通过基因表达分析，鉴定人类冬眠心肌特有的新型分子机制。
结果：在检测的4171个转录本（transcripts）中，我们鉴定出86个差异表达转录本。其中21个基因在冬眠心肌中表达上调，65个基因表达下调。功能聚类分析显示，与转录调控、蛋白质修饰及磷酸化、细胞凋亡调控以及细胞间通讯相关的基因表达发生显著改变。除此前报道的心力衰竭中β-肾上腺素能受体激酶-1（ß-adrenergic receptor kinase-1）的上调外，我们还观察到新的基因表达模式，例如fas激活的丝氨酸/苏氨酸激酶（fas-activated serine/threonine kinase, FAST）的上调，以及桥粒斑蛋白（desmoplakin）的表达降低。在冬眠心肌来源的心肌细胞中，桥粒斑蛋白的下调在蛋白水平也得到了证实，这与该蛋白在扩张型心肌病（dilative cardiomyopathy）发生发展中的作用相符。
结论：对冬眠心肌的基因表达分析为缺血性心力衰竭（ischemic heart failure）的潜在分子机制提供了全新见解。桥粒（desmosomes）功能异常可能参与了收缩功能受损及扩张性组织重构的进程。
关键词：疾病状态分析（disease state analysis）
方法：我们对比了晚期冠状动脉疾病（coronary artery disease）伴左心室功能受损患者的两类心肌活检组织的基因表达谱：一类是经PET显像显示灌注与葡萄糖代谢不匹配而鉴定出的冬眠心肌活检组织（n=5），另一类是配对的远端心肌活检组织。我们通过选定基因的基因特异性PCR验证了本研究的技术方案，并针对1个特定关注基因开展了免疫组化染色（immunohistochemical staining）。