Lee Soon Jin, Ways Justin A, Barbato John C, Essig David, Pettee Krista, DeRaedt Sarah J, Yang Siming, Weaver David A, Koch Lauren G, Cicila George T
Department of Physiology and Cardiovascular Genomics, Medical University of Ohio, Toledo, Ohio 43614, USA.
Physiol Genomics. 2005 Sep 21;23(1):62-71. doi: 10.1152/physiolgenomics.00251.2004. Epub 2005 Jul 20.
Our previous work found DA rats superior for intrinsic aerobic running capacity (ARC) and several cardiac function indexes compared with Copenhagen (COP) rats, and identified ARC quantitative trait loci (QTLs) on rat chromosomes 16 (RNO16) and 3 (RNO3). The purpose of this study was to use these inbred rat strains as a genetic substrate for differential cardiac gene expression to identify candidate genes for the observed ARC QTLs. RNA expression was examined globally in left ventricles of 15-wk-old DA, F1(COP x DA), and COP rats using microarrays to identify candidate genes for ARC QTLs. We identified 199 differentially expressed probe sets and determined their chromosomal locations. Six differentially expressed genes and expressed sequence tags (ESTs) mapped near ARC QTL regions, including PDZ and LIM domain 3 (Pdlim3). Differential expression of these genes/ESTs was confirmed by quantitative RT-PCR. The Ingenuity Pathways program identified 13 biological networks containing 50 (of the 199) differentially expressed probe sets and 85 additional genes. Four of these eighty-five genes mapped near ARC QTL-containing regions, including insulin receptor substrate 2 (Irs2) and acyl-CoA synthetase long-chain family member 1 (Acsl1). Most (148/199) differentially expressed probe sets showed left ventricular expression patterns consistent with the alleles exerting additive effects, i.e., F1(COP x DA) rat RNA expression was intermediate between DA and COP rats. This study identified several potential ARC QTL candidate genes and molecular networks, one of them related to energy expenditure involving Pik3r1 mRNA expression that may, in part, explain the observed strain differences in ARC and cardiac performance.
我们之前的研究发现，与哥本哈根（COP）大鼠相比，DA大鼠在内源性有氧跑步能力（ARC）和多项心脏功能指标方面更具优势，并在大鼠16号染色体（RNO16）和3号染色体（RNO3）上确定了ARC数量性状基因座（QTL）。本研究的目的是利用这些近交系大鼠品系作为心脏基因差异表达的遗传底物，以鉴定观察到的ARC QTL的候选基因。使用微阵列对15周龄的DA、F1（COP×DA）和COP大鼠的左心室进行全基因组RNA表达检测，以鉴定ARC QTL的候选基因。我们鉴定出199个差异表达的探针集，并确定了它们的染色体位置。六个差异表达基因和表达序列标签（EST）定位于ARC QTL区域附近，包括PDZ和LIM结构域3（Pdlim3）。通过定量RT-PCR证实了这些基因/EST的差异表达。Ingenuity Pathways程序确定了13个生物网络，其中包含199个差异表达探针集中的50个以及另外85个基因。这85个基因中有4个定位于含ARC QTL的区域附近，包括胰岛素受体底物2（Irs2）和酰基辅酶A合成酶长链家族成员1（Acsl1）。大多数（148/199）差异表达探针集显示出与发挥加性效应的等位基因一致的左心室表达模式，即F1（COP×DA）大鼠的RNA表达介于DA和COP大鼠之间。本研究鉴定出了几个潜在的ARC QTL候选基因和分子网络，其中一个与能量消耗有关，涉及Pik3r1 mRNA表达，这可能部分解释了观察到的ARC和心脏功能方面的品系差异。
