SPARC-Dependent Cardiomyopathy in Drosophila.
SPARC-Dependent Cardiomyopathy in Drosophila.
复制标题
DOI：
10.1161/circgenetics.115.001254
复制
发表时间：
2016-04
期刊：
影响因子：
--
通讯作者：
Ocorr K
中科院分区：
文献类型：
--
作者：
Hartley PS;Motamedchaboki K;Bodmer R;Ocorr K
补充数字内容可在文本中找到。果蝇心脏是研究哺乳动物心脏功能遗传基础的重要模型。该系统包括收缩性心肌细胞，其附近是通过未表征的机制调节心脏功能的高度内吞的心包肾细胞对。确定这些机制和相关分子是重要的，因为它们可能与人类心脏生理学有关。这项工作的目的是确定循环心脏调节因子的潜在相关性，人类使用果蝇肾细胞心肌细胞系统。Kruppel样因子15（dKlf 15）功能丧失策略用于消融肾细胞，然后分析心脏功能和血淋巴蛋白质组。肾细胞消融导致严重的心肌病，其特征是舒张间期延长。通过破坏它们的内吞功能或暂时条件性敲低dKlf 15使成年肾细胞功能障碍导致类似的心肌病。蛋白质组学揭示，肾细胞调节许多分泌蛋白的循环水平，其中最显著的是进化上保守的基质细胞蛋白酸性和富含半胱氨酸的分泌蛋白（Secreted Protein Acidic and Rich in Cysteine，缩写为Cys），一种参与哺乳动物心脏功能的蛋白质。最后，减少β-淀粉样蛋白基因的剂量可以改善在缺乏肾细胞的情况下发生的心肌病。这些数据暗示了果蝇心脏功能的非细胞自主控制，并表明调节cardiac基因的表达可能会改善人类的心功能障碍。
Supplemental Digital Content is available in the text. The Drosophila heart is an important model for studying the genetics underpinning mammalian cardiac function. The system comprises contractile cardiomyocytes, adjacent to which are pairs of highly endocytic pericardial nephrocytes that modulate cardiac function by uncharacterized mechanisms. Identifying these mechanisms and the molecules involved is important because they may be relevant to human cardiac physiology. This work aimed to identify circulating cardiomodulatory factors of potential relevance to humans using the Drosophila nephrocyte–cardiomyocyte system. A Kruppel-like factor 15 (dKlf15) loss-of-function strategy was used to ablate nephrocytes and then heart function and the hemolymph proteome were analyzed. Ablation of nephrocytes led to a severe cardiomyopathy characterized by a lengthening of diastolic interval. Rendering adult nephrocytes dysfunctional by disrupting their endocytic function or temporally conditional knockdown of dKlf15 led to a similar cardiomyopathy. Proteomics revealed that nephrocytes regulate the circulating levels of many secreted proteins, the most notable of which was the evolutionarily conserved matricellular protein Secreted Protein Acidic and Rich in Cysteine (SPARC), a protein involved in mammalian cardiac function. Finally, reducing SPARC gene dosage ameliorated the cardiomyopathy that developed in the absence of nephrocytes. The data implicate SPARC in the noncell autonomous control of cardiac function in Drosophila and suggest that modulation of SPARC gene expression may ameliorate cardiac dysfunction in humans.