Abstract
Titin isoform expression is related to human cardiac disease. A mutant rat model with dramatically altered titin isoform expression has been described (Greaser et al. J Mol. Cell. Cardiol. 44:483, 2009), and the ultrastructural and physiological properties of mutant and wild type rats were compared in this study. Electron micrographs of homozygous mutant ventricles showed normal structure in most areas, but occasional regions of Z line streaming, myofibrillar disarray, lipofuchin granules, and myofibril degeneration were observed as found previously in human heart failure. Dobutamine administration caused an increased heart rate in wild type (Wt), heterozygotes (Ht) and homozygote mutants (Hm), but the dobutamine effects on preload recruitable stroke work and maximal systolic elastance were significantly blunted in the mutant groups. Maximal exercise capacity of Wt rats was significantly longer than that of Hm. Electrophoretic myosin heavy chain analysis of left ventricle (LV) samples showed no differences between Wt, Ht, or Hm in the beta myosin heavy chain proportions. Gene expression patterns in LV were conducted with Affymetrix GeneChip Rat Genome 230 2.0 microarrays using WT and Hm LV at three developmental stages (day 1, day 20 and day 49). A Student t-test with a p value cut-off of 0.05 and a minimum 1.5-fold change reveals changes in 372 mutation-specific transcripts (188 known and 96 un-annotated genes). A number of titin associated genes were up-regulated (Myot, T-cap, DARP, FHL1), and this up-regulation was verified by QPCR. Hierarchical clustering revealed gene expression patterns of Wt and Hm LV were related to their titin protein gel pattern. Predefined pathways and functional categories annotated by KEGG, Biocarta, and GO using the DAVID bioinformatic resource indicated involvement of TGF Beta 2, CTGF-regulated fibrosis, Trdn-Casq interaction-regulated RyR channel, and cAMP-dependent pathways. Supported by NIH HL77196.
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