Global Proteomics and Pathway Analysis of Pressure-Overload-Induced Heart Failure and Its Attenuation by Mitochondrial-Targeted Peptides
Global Proteomics and Pathway Analysis of Pressure-Overload-Induced Heart Failure and Its Attenuation by Mitochondrial-Targeted Peptides
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DOI：
10.1161/circheartfailure.113.000406
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发表时间：
2013-09-01
影响因子：
9.7
通讯作者：
Rabinovitch, Peter S.
中科院分区：
文献类型：
--
作者：
Dai, Dao-Fu;Hsieh, Edward J.;Rabinovitch, Peter S.
背景我们研究了线粒体靶向的抗氧化剂和保护性多肽Szeto-Schiller(SS)31和SS20对心功能、蛋白质组重构和信号通路的保护作用。方法和结果我们应用改良的无标记鸟枪蛋白质组学方法，利用独创性通路分析来评估横动脉缩窄(TAC)所致心力衰竭时整体蛋白质组学的变化及其相关的信号通路变化。我们发现，538个蛋白质在TAC后发生了显著的变化，这些蛋白质定位于53条途径。最重要的途径是肌动蛋白细胞骨架、线粒体功能、中间代谢、糖酵解/糖异生和柠檬酸循环。SS31可改善TAC所致的充血性心力衰竭表型和线粒体损伤，线粒体蛋白质组改变总体减弱，平均保护线粒体84%，非线粒体蛋白改变69%。这包括对上面提到的所有独创性途径分析的显著改进。SS20对心力衰竭的影响不大，整体蛋白质组学改变仅部分减弱；此外，SS20对肌动蛋白细胞骨架通路有明显的保护作用，而线粒体和代谢通路基本不受保护。结论本研究阐明了压力超负荷所致心力衰竭时信号通路的显著改变。线粒体靶向多肽SS31对TAC诱导的蛋白质组改变的整体减弱表明，线粒体功能紊乱可能是TAC许多途径改变的上游信号，并支持线粒体靶向多肽药物治疗心力衰竭的潜在临床应用。
Background We investigated the protective effects of mitochondrial-targeted antioxidant and protective peptides, Szeto-Schiller (SS) 31 and SS20, on cardiac function, proteomic remodeling, and signaling pathways.Methods and Results We applied an improved label-free shotgun proteomics approach to evaluate the global proteomics changes in transverse aortic constriction (TAC)-induced heart failure and the associated signaling pathway changes using ingenuity pathway analysis. We found that 538 proteins significantly changed after TAC, which mapped to 53 pathways. The top pathways were in the categories of actin cytoskeleton, mitochondrial function, intermediate metabolism, glycolysis/gluconeogenesis, and citrate cycle. Concomitant treatment with SS31 ameliorated the congestive heart failure phenotypes and mitochondrial damage induced by TAC, in parallel with global attenuation of mitochondrial proteome changes, with an average of 84% protection of mitochondrial and 69% of nonmitochondrial protein changes. This included significant amelioration of all the ingenuity pathway analysis noted above. SS20 had only modest effects on heart failure and this tracked with only partial attenuation of global proteomics changes; furthermore, actin cytoskeleton pathways were significantly protected in SS20, whereas mitochondrial and metabolic pathways essentially were not.Conclusions This study elucidates the signaling pathways significantly changed in pressure-overload-induced heart failure. The global attenuation of TAC-induced proteomic alterations by the mitochondrial-targeted peptide SS31 suggests that perturbed mitochondrial function may be an upstream signal to many of the pathway alterations in TAC and supports the potential clinical application of mitochondrial-targeted peptide drugs for the treatment heart failure.