Gene expression profiling of the left ventricles in a rat model of intrinsic aerobic running capacity

Abstract

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.

Congenic strains confirm aerobic running capacity quantitative trait loci on rat chromosome 16 and identify possible intermediate phenotypes

“…2), consistent with our previous results (1,19,23,39). COP.DA(chr 16) rats had a significantly greater mean best distance run to exhaustion of 696.7 Ϯ 38.2 m compared with COP rats (P ϭ 0.03; Fig.…”

“…Our laboratory has consistently found greater heart and left ventricular weights for the high-performing DA strain compared with the low-performing COP strain (1,19,23,39). Expression profiling of the left ventricles of these strains also identified two networks of coordinately regulated, differentially expressed genes whose annotations suggested involvement in cell growth, metabolism, death, and differentiation (23).…”

“…Expression profiling of the left ventricles of these strains also identified two networks of coordinately regulated, differentially expressed genes whose annotations suggested involvement in cell growth, metabolism, death, and differentiation (23). Findings of higher isolated cardiac function for DA, compared with COP rats (1), as well as divergence for a number of related phenotypes (8, 19) described above, further implicate functional cardiac differences as likely contributors to ARC.…”

“…However, these physiological strain differences have not been linked to any specific chromosomal region, making it difficult to identify a contributing genetic factor. In addition, a number of RNA sequences were found differentially expressed between the left ventricles of COP and DA rats, indicating differences in cardiac gene regulation (23). Two of these differentially expressed genes include phosphatidylinositol 3-kinase, regulatory subunit 1 (Pik3r1) and the rat ortholog of human myosin light chain 2a gene (MLC2a), which both showed Ͼ14-fold differences in RNA expression levels but did not map near ARC QTLs.…”

The Right Heart and Its Distinct Mechanisms of Development, Function, and Failure

“…A number of studies have indicated that gender differences play a role in the overall response to sepsis and hemorrhage, as well as in the functional recovery of endotoxin associated left heart dysfunction [82][83][84][85][86]. In these instances, females tend to have a higher degree of cardioprotection and lower levels of proinflammatory cytokines compared to their male counterparts [6,78,87].…”