Age- and Hypertension-Associated Protein Aggregates in Mouse Heart Have Similar Proteomic Profiles.
Age- and Hypertension-Associated Protein Aggregates in Mouse Heart Have Similar Proteomic Profiles.
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DOI：
10.1161/hypertensionaha.115.06849
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发表时间：
2016-05
期刊：
影响因子：
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通讯作者：
Mehta JL
中科院分区：
文献类型：
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作者：
Ayyadevara S;Mercanti F;Wang X;Mackintosh SG;Tackett AJ;Prayaga SV;Romeo F;Shmookler Reis RJ;Mehta JL
神经退行性疾病主要由受影响组织中的蛋白质聚集体定义。聚集体包含一些共有的成分以及被认为对每种疾病特异的蛋白质。聚集以前没有报道在正常，老化的心脏或高血压心脏。洗涤剂不溶性蛋白质聚集体从小鼠心脏中分离，并在2D凝胶上表征。随着年龄的增长和持续的血管紧张素II诱导的高血压，它们的水平显着增加。在高分辨率蛋白质组学鉴定的聚集组分中，一半随着年龄（392/787）或持续高血压（459/824）而变化，而30%（273/901）在两者中变化一致，每个P<0.05。这些蛋白质中的五分之一先前与年龄进行性神经变性和/或心血管疾病相关-例如ApoE、ApoJ、ApoA-IV、丛生蛋白、补体C3以及参与应激反应和蛋白质稳态途径的其他蛋白质。由于纤维化是老年和高血压心脏的特征，我们假设成纤维细胞的老化可能有助于在心脏组织中观察到的聚集体。事实上，随着心脏肌成纤维细胞在体外“衰老”（接近其复制极限），它们积累了许多在自然衰老或持续高血压期间在体内观察到的相同组成蛋白的聚集体。总之，我们首次发现，在自然衰老、慢性高血压和体外肌成纤维细胞衰老过程中，致密（洗涤剂不溶性）蛋白质聚集体积累，共享许多共同的蛋白质。因此，由不同原因（衰老、高血压、复制性衰老）引起的聚集体可能具有共同的潜在累积机制。
Neurodegenerative diseases are largely defined by protein aggregates in affected tissues. Aggregates contain some shared components as well as proteins thought to be specific for each disease. Aggregation has not previously been reported in the normal, aging heart or the hypertensive heart. Detergent-insoluble protein aggregates were isolated from mouse heart and characterized on 2D gels. Their levels increased markedly and significantly with aging and following sustained angiotensin-II-induced hypertension. Of the aggregate components identified by high-resolution proteomics, half changed in abundance with age (392/787) or with sustained hypertension (459/824), while 30% (273/901) changed concordantly in both, each P<0.05. One fifth of these proteins were previously associated with age-progressive neurodegenerative and/or cardiovascular diseases — e.g. ApoE, ApoJ, ApoA-IV, clusterin, complement C3, and others involved in stress-response and protein-homeostasis pathways. Since fibrosis is a characteristic of both aged and hypertensive hearts, we posited that aging of fibroblasts may contribute to the aggregates observed in cardiac tissue. Indeed, as cardiac myofibroblasts “senesced” (approached their replicative limit) in vitro, they accrued aggregates with many of the same constituent proteins observed in vivo during natural aging or sustained hypertension. In summary, we have shown for the first time that compact (detergent-insoluble) protein aggregates accumulate during natural aging, chronic hypertension and in vitro myofibroblast senescence, sharing many common proteins. Thus, aggregates that arise from disparate causes (aging, hypertension, replicative senescence) may have common underlying mechanisms of accrual.