Cand2 links pathological mTORC1 signaling to adverse cardiac remodeling by regulating Grk5 expression. Cand2 links pathological mTORC1 signaling to adverse cardiac remodeling by regulating Grk5 expression

The mechanistic target of rapamycin (mTOR) is a key regulator of pathological remodeling in the heart by activating ribosomal biogenesis and mRNA translation. Inhibition of mTOR in cardiomyocytes is protective, however, a detailed role of mTOR in translational regulation of specific mRNA networks in the diseased heart is largely unknown. A cardiomyocyte genome-wide sequencing approach was used to define mTOR-dependent post-transcriptional gene expression control at the level of mRNA translation. This approach identified the muscle specific protein Cullin-associated NEDD8-dissociated protein 2 (Cand2) as a translationally upregulated gene dependent on the activity of mTOR. Deletion of Cand2 protects the myocardium against pathological remodeling. Mechanistically, we found that Cand2 links mTOR- signaling to pathological cell growth by increasing Grk5 protein expression. Our data suggest that cell-type specific targeting of mTOR might have therapeutic value for adverse pathological cardiac remodeling. Overall design: Comparision of WT mice vs global Cand2 KO mice

雷帕霉素机制靶标（mechanistic target of rapamycin, mTOR）是心脏病理性重构的关键调控因子，其通过激活核糖体生物发生与信使RNA（mRNA）翻译过程发挥调控作用。尽管在心肌细胞中抑制mTOR可起到保护作用，但目前对于mTOR在患病心脏内特定mRNA网络的翻译调控中所扮演的具体角色仍知之甚少。本研究采用心肌细胞全基因组测序方法，明确了mRNA翻译层面上依赖于mTOR的转录后基因表达调控机制。本研究通过该方法鉴定出肌肉特异性蛋白Cullin结合NEDD8解离蛋白2（Cullin-associated NEDD8-dissociated protein 2, Cand2）为受mTOR活性调控、翻译水平上调的基因。敲除Cand2可使心肌组织免受病理性重构的损伤。机制研究显示，Cand2通过上调G蛋白偶联受体激酶5（Grk5）的蛋白表达，将mTOR信号通路与病理性细胞生长相关联。本研究数据表明，针对细胞类型特异性的mTOR靶向干预，或可在不良病理性心脏重构的治疗中具备应用价值。整体实验设计：野生型（Wild Type, WT）小鼠与全身Cand2基因敲除（Knock Out, KO）小鼠的对照实验