Abstract

In order to get further insight upon the effects of Thyroid hormone (T3) in the heart, we have used a microarray approach to identify responsive genes in rats submitted to T3 injections for 12, 24h and 7 days. Firstly, we have compared 5 different algorithms to analyze microarray data and found MAS5 to be the best fit in our model. We have detected novel responsive genes at the intercalated disk and sarcomere M‐band levels. qRT‐PCR analysis and western blot confirmed a transient increase in cadherin‐13 expression (2.7 fold for qRT‐PCR and 2.4 for Western Blot, both p<0.05) peaking at 24 hours of T3 treatment and a progressive decrease of M‐protein gene expression (0.2 fold, p <0.05, at 7 days of T3 treatment). Because M‐protein is a structural sarcomeric protein and has a predicted role in sarcomere stability we decided to further investigate cellular/molecular mechanisms. M‐protein is up regulated in hypothyroidism (3.4 fold) and repressed by T3 in a dose dependent manner in vivo and also in cultured neonatal cardiomyocytes. Reporter assays revealed that the M‐protein promoter is responsive to T3. siRNA M‐protein knock down showed reduced contractility, highlighting the importance of this protein for sarcomere stability. We conclude that T3 quickly and strongly repress M‐protein at the transcriptional level, which might help to explain the long‐term deleterious effects of T3 in the heart.Grant Funding Source: FAPESP and CNPq

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