Schechter Matthew A, Hsieh Michael K H, Njoroge Linda W, Thompson J Will, Soderblom Erik J, Feger Bryan J, Troupes Constantine D, Hershberger Kathleen A, Ilkayeva Olga R, Nagel Whitney L, Landinez Gina P, Shah Kishan M, Burns Virginia A, Santacruz Lucia, Hirschey Matthew D, Foster Matthew W, Milano Carmelo A, Moseley M Arthur, Piacentino Valentino, Bowles Dawn E
Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America.
Duke Proteomics Core, Duke University Medical Center, Durham, North Carolina, United States of America.
PLoS One. 2014 Aug 12;9(8):e104157. doi: 10.1371/journal.pone.0104157. eCollection 2014.
The molecular differences between ischemic (IF) and non-ischemic (NIF) heart failure are poorly defined. A better understanding of the molecular differences between these two heart failure etiologies may lead to the development of more effective heart failure therapeutics. In this study extensive proteomic and phosphoproteomic profiles of myocardial tissue from patients diagnosed with IF or NIF were assembled and compared. Proteins extracted from left ventricular sections were proteolyzed and phosphopeptides were enriched using titanium dioxide resin. Gel- and label-free nanoscale capillary liquid chromatography coupled to high resolution accuracy mass tandem mass spectrometry allowed for the quantification of 4,436 peptides (corresponding to 450 proteins) and 823 phosphopeptides (corresponding to 400 proteins) from the unenriched and phospho-enriched fractions, respectively. Protein abundance did not distinguish NIF from IF. In contrast, 37 peptides (corresponding to 26 proteins) exhibited a ≥ 2-fold alteration in phosphorylation state (p<0.05) when comparing IF and NIF. The degree of protein phosphorylation at these 37 sites was specifically dependent upon the heart failure etiology examined. Proteins exhibiting phosphorylation alterations were grouped into functional categories: transcriptional activation/RNA processing; cytoskeleton structure/function; molecular chaperones; cell adhesion/signaling; apoptosis; and energetic/metabolism. Phosphoproteomic analysis demonstrated profound post-translational differences in proteins that are involved in multiple cellular processes between different heart failure phenotypes. Understanding the roles these phosphorylation alterations play in the development of NIF and IF has the potential to generate etiology-specific heart failure therapeutics, which could be more effective than current therapeutics in addressing the growing concern of heart failure.
缺血性（IF）和非缺血性（NIF）心力衰竭之间的分子差异尚不明确。更好地了解这两种心力衰竭病因之间的分子差异可能会推动更有效的心力衰竭治疗方法的开发。在本研究中，我们收集并比较了诊断为IF或NIF的患者心肌组织的广泛蛋白质组和磷酸化蛋白质组图谱。从左心室切片中提取的蛋白质经蛋白酶解，磷酸肽使用二氧化钛树脂进行富集。凝胶和无标记的纳米级毛细管液相色谱与高分辨率精确质量串联质谱联用，分别对未富集和磷酸化富集组分中的4436个肽段（对应450种蛋白质）和823个磷酸肽段（对应400种蛋白质）进行了定量分析。蛋白质丰度无法区分NIF和IF。相比之下，在比较IF和NIF时，37个肽段（对应26种蛋白质）的磷酸化状态发生了≥2倍的变化（p<0.05）。这37个位点的蛋白质磷酸化程度具体取决于所检查的心力衰竭病因。表现出磷酸化改变的蛋白质被归类为功能类别：转录激活/RNA加工；细胞骨架结构/功能；分子伴侣；细胞粘附/信号传导；细胞凋亡；以及能量/代谢。磷酸化蛋白质组分析表明，不同心力衰竭表型中参与多种细胞过程的蛋白质存在深刻的翻译后差异。了解这些磷酸化改变在NIF和IF发展中所起的作用，有可能产生针对病因的心力衰竭治疗方法，在解决日益严重的心力衰竭问题方面可能比目前的治疗方法更有效。
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