Time dependence of volume overload on left ventricular remodeling during preadolescence

We reported the RNAseq analyses of left ventricualr free wall myocardium in young volume overload (VO) C57/BL6 mice.VO was induced by the fistula between abdominal aorta and inferior vena cava (AVF) on postnatal day 7(P7). RNAseq analyses of LV free wall at P14 and P21from VO and sham-operated mice revealed that there were 378 differentially expressed genes between VO and sham group at P14, this number decreased to 184 at P21, there were 1374 differentially expressed genes between P21 and P14 sham group, and the number chenged to 1167 at the presence of VO. GO analysis showed that in the VO and sham comparison, the upregulated genes mainly mediated cell-cell junction and the downregulated genes mainly mediated regulation of immune response at P14, and the upregulated genes mainly mediated cell growth, and downregulated genes mainly mediated response to interferon-beta at P21. As expected, in the normal LV development during preadolescence (from P14 to P21), upregulated genes mainly mediated muscle system process and regulation of membrane potential and the downregulated genes mainly mediated regulation of mitotic cell cycle. VO changed the LV development, the upregulated genes mainly mediated regulation of protein catabolic process and the down regulated genes mainly mediated antigen processing and presentation. KEGG pathway analysis revealed that glucagon signaling pathway was upregulated and phagosome pathway and chemokine signaling pathway were downregulated between VO and sham group at P14, protein processing in endoplasmic reticulum was upregulated and antigen processing and presentation were downregulated at P21 between VO and sham group. In the normal LV development, calcium signaling pathway and cardiac muscle contraction pathway were upregulated while VO changed that to the arginine and proline metabolism . All the above changes were further confirmed by the functional tests. Overall design: RNAseq analyses of left ventricular free wall myocardium in young volume overload and sham-operated C57/BL6 mice

本研究报道了幼年容量超负荷（volume overload, VO）型C57/BL6小鼠左心室（left ventricular, LV）游离壁心肌的RNA测序（RNAseq）分析结果。该模型于小鼠出生后第7天（P7）通过腹主动脉与下腔静脉间的瘘管（abdominal aortocaval fistula, AVF）构建。对容量超负荷组与假手术（sham）组小鼠在出生后第14天（P14）及第21天（P21）的左心室游离壁组织进行RNA测序分析，结果显示：P14时，容量超负荷组与假手术组间存在378个差异表达基因；至P21时，该差异基因数量降至184个。P21与P14假手术组间存在1374个差异表达基因，而在容量超负荷造模状态下，该数值变为1167个。基因本体（Gene Ontology, GO）富集分析结果表明：在P14时，容量超负荷组与假手术组的比较中，上调差异基因主要参与细胞间连接相关生物学过程，下调差异基因主要参与免疫应答调控过程；而在P21时，上调差异基因主要参与细胞生长过程，下调差异基因主要参与β干扰素应答过程。如预期一致，在青春前期左心室正常发育过程中（P14至P21），上调差异基因主要参与肌肉系统过程与膜电位调控过程，下调差异基因主要参与有丝分裂细胞周期调控过程。容量超负荷造模改变了左心室正常发育进程：此时上调差异基因主要参与蛋白质分解代谢调控过程，下调差异基因主要参与抗原加工与呈递过程。京都基因与基因组百科全书（Kyoto Encyclopedia of Genes and Genomes, KEGG）通路富集分析结果显示：P14时，容量超负荷组与假手术组相比，胰高血糖素信号通路呈上调趋势，吞噬体通路与趋化因子信号通路呈下调趋势；P21时，内质网蛋白质加工通路呈上调趋势，抗原加工与呈递通路呈下调趋势。在正常左心室发育过程中，钙信号通路与心肌收缩通路呈上调趋势，但容量超负荷造模使该表达模式发生改变，此时上调通路变为精氨酸与脯氨酸代谢通路。上述所有表达变化均通过功能实验得到进一步验证。实验整体设计：幼年容量超负荷型与假手术型C57/BL6小鼠左心室游离壁心肌的RNA测序分析。