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.

Substitution mapping was used to refine the localization of blood pressure (BP) quantitative trait loci (QTL) within the congenic region of S.R-Edn3 rats located at the q terminus of rat chromosome 3 (RNO3). An F 2 (S 3 S.R-Edn3) population (n ¼ 173) was screened to identify rats having crossovers within the congenic region of RNO3 and six congenic substrains were developed that carry shorter segments of R-rat-derived RNO3. Five of the six congenic substrains had significantly lower BP compared to the parental S rat. The lack of BP lowering effect demonstrated by the S.R(ET3 3 5) substrain and the BP lowering effect retained by the S.R(ET3 3 2) substrain together define the RNO3 BP QTL-containing region as $4.64 Mb. Two nonoverlapping substrains, S.R(ET3 3 1) and S.R(ET3 3 6), had significantly lower BP compared to the S strain, indicating the presence of two distinct BP QTL in the RNO3 q terminus. The RNO3 q terminus was fine mapped with newly developed polymorphic markers to characterize the extent of the congenic regions. The two RNO3 BP QTL regions were thus defined as within intervals of 0.05-1.12 and 0.72-1.25 Mb, respectively. Also important was our difficulty in fine mapping and marker placement in this portion of the rat genome (and thus candidate gene identification) using the available genomic data, including the rat genome sequence.

Neointimal Hyperplasia (NIH) can lead to restenosis after clinical vascular interventions. NIH results from complex, and poorly understood, interactions between signaling cascades in the extracellular matrix and disrupted endothelium which leads to vessel occlusion. Quantitative Trait Loci (QTLs) were previously reported on rat chromosomes 3 and 6 through linkage analysis of post-injury NIH in mid-iliac arterial sections. In the current study, substitution mapping validated the RNO3 NIH QTL but not the RNO6 NIH QTL. The SHR.BN3 congenic strain had a three-fold increase in %NIH compared to the parental SHR strain. A double congenic study of RNO3+RNO6 NIH QTL segments suggested less than additive effects of these two genomic regions. To test the hypothesis that changes in vessel dynamics account for the differences in NIH formation, we performed vascular reactivity studies in the BN, SHR, SHR.BN3 and SHR.BN6 strains. De-endothelialized left common carotid artery rings of the SHR.BN3 showed an increased vascular responsiveness when treated with serotonin or prostaglandin F2α, with significant differences in EC50 and Emax (p < 0.01) values compared to the SHR parental strain. Since both vascular reactivity and %NIH formation in the SHR.BN3 strain are significantly higher than the SHR strain, we postulate that these traits may be associated and are controlled by genetic elements on RNO3. In summary, these results confirm that the RNO3 NIH QTL carries the gene(s) contributing to post-injury NIH formation.

December 19, 2006; doi:10.1152/physiolgenomics.00027.2006.-We previously identified two inbred rat strains divergent for treadmill aerobic running capacity (ARC), the low-performing Copenhagen (COP) and the high-performing DA rats, and used an F2(COPϫDA) population to identify ARC quantitative trait loci (QTLs) on rat chromosome 16 (RNO16) and the proximal portion of rat chromosome 3 (RNO3). Two congenic rat strains were bred to further investigate these ARC QTLs by introgressing RNO16 and the proximal portion of RNO3 from DA rats into the genetic background of COP rats and were named COP.DA(chr 16) and COP.DA(chr 3), respectively. COP.DA(chr 16) rats had significantly greater ARC compared with COP rats (696.7 Ϯ 38.2 m vs. 571.9 Ϯ 27.5 m, P ϭ 0.03). COP.DA(chr 3) rats had increased, although not significant, ARC compared with COP rats (643.6 Ϯ 40.9 m vs. 571.9 Ϯ 27.5 m). COP.DA(chr 16) rats had significantly greater subcutaneous abdominal fat, as well as decreased fasting triglyceride levels, compared with COP rats (P Ͻ 0.05), indicating that genes responsible for strain differences in fat metabolism are also located on RNO16. While this colocalization of QTLs may be coincidental, it is also possible that these differences in energy balance may be associated with the superior running performance of COP.DA(chr 16) consomic rats. treadmill endurance test; abdominal fat; subcutaneous abdominal fat; consomic; triglycerides TREADMILL EXERCISE TESTS MEASURE the integrative capability of multiple physiological systems to influence the overall adaptation to a bout of exercise and are often used to assess overall health and predict mortality (13,22,30). The greater the functional capacity of each system, the more efficiently an individual will adapt to the exercise, leading to a greater aerobic performance. Similarly, systems with a diminished functional capacity will be less capable of adapting to exercise stress, leading to decreased aerobic performance, and may reflect an increased susceptibility to disease development.Treadmill running capacity is a complex trait where the interactions of multiple genetic and environmental factors influence overall performance (5). The genetic component explains a large amount of variation in performance within a given population, with human and rodent studies estimating the heritability of exercise performance to range from 39.0 to 73.0% (4,19,24,25). This genetic component likely results from a complex mixture of multiple genes, with each exerting relatively minor effects on performance (2-4, 15, 19, 24, 25). We may be able to improve the likelihood of observing effects from major genes if we dissect this running performance trait into simpler, less complex, phenotypes. This would facilitate identification of genes regulating aerobic running capacity (ARC) as well as the molecular pathways through which they function.Congenic and consomic strains have proven useful in confirming and delimiting the locations of quantitative trait loci (QTLs), as well as reducing the complexity of ...

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