Great Dane Dilated Cardiomyopathy is Associated with Altered Triadin and Calstabin2 Transcription
ACVIM 2008
M.A. Oyama1; C.R. Reynolds1; M. Kuentzel2; S.V. Chittur2
1Department of Clinical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA; 2Center for Functional Genomics, State University of New York, Albany, NY, USA

Little is known regarding the molecular mechanisms underlying dilated cardiomyopathy (DCM) in the Great Dane. Thus, we performed a widescale evaluation of transcriptional activity from myocardial tissue of affected dogs. cRNA was generated from left ventricular tissues from 3 Great Danes that were euthanized due to refractory DCM and from 3 large breed dogs euthanized for non-cardiac reasons and hybridized to a second generation canine-specific microarray (Canine GeneChip 2.0, Affymetrix). Comparison of transcriptional activity revealed significant downregulation of 24 transcripts and upregulation of 298 transcripts in affected dogs vs control. The two transcripts with the greatest differential expression were triadin (9.07-fold down-regulated) and calstabin2 (FKBP12.6) (61.3-fold up-regulated). Expression of these two transcripts was further investigated using RT-qPCR. Both triadin and calstabin2 are regulators of cardiac ryanodine receptor (RYR2) activity and hence, movement of Ca2+ within myocardial cells. Triadin is a transmembrane protein that links RYR2 to calsequestrin and is a critical determinant of systolic Ca2+ release from the sarcoplasmic reticulum. Triadin deficiency would putatively lead to reduced calsequestrin-RYR2 binding, "leaky" RYR2, and decreased efficiency of excitation-contraction coupling. Calstabin2 binds to the cytoplasmic domain of RYR2 and promotes a closed RYR2 state, thus increased expression of calstabin2 may represent a compensatory response. Further study involving calcium transients, RYR2 function, and the role of triadin and calstabin2 in Great Dane DCM is warranted.

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Mark Oyama, DVM, DACVIM (Cardiology)
Philadelphia, PA


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