The main research focus is the role of thyroid hormone metabolism in heart failure. Multiple signal-transduction pathways have been shown to be involved in the process of pathological hypertrophy and heart failure, and one of the factors that may play a role is reduced thyroid-hormone (TH) signaling. A condition of low TH-levels is characterized by a cardiac gene expression pattern that resembles that of the pathologically remodeling heart. Our group reported an almost complete impairment of cardiomyocyte-specific TH signaling in hypertension-induced RV failure in the rat as well as in chronic LV failure following myocardial infarction in mice. In both models this is associated with the re-induction in cardiomyocytes of the TH-degrading enzyme deiodinase type 3 (Dio3) and, as a result, reduced TH activity. Our current research is aimed at establishing the mechanism of Dio3 induction and the role of reduced cardiac TH signaling in pathological gene expression and cardiac dysfunction in chronic heart failure.
MicroRNA 214 Is a Potential Regulator of Thyroid Hormone Levels in the Mouse Heart Following Myocardial Infarction, by Targeting the Thyroid-Hormone-Inactivating Enzyme Deiodinase Type III. Janssen R, Zuidwijk MJ, Muller A, van Mil A, Dirkx E, Oudejans CB, Paulus WJ,Simonides WS. Front Endocrinol. 2016; 7:22.
Janssen R, Zuidwijk MJ, Kuster DW, Muller A, Simonides WS. Thyroid Hormone-Regulated Cardiac microRNAs are Predicted to Suppress Pathological Hypertrophic Signaling. Front Endocrinol. 2014; 5:171.
Janssen R, Zuidwijk M, Muller A, Mulders J, Oudejans CB, Simonides WS. Cardiac expression of deiodinase type 3 (Dio3) following myocardial infarction is associated with the induction of a pluripotency microRNA signature from the Dlk1-Dio3 genomic region. Endocrinology. 2013; 154:1973-1978.
Pol CJ, Muller A, Zuidwijk MJ, van Deel ED, Kaptein E, Saba A, Marchini M, Zucchi R, Visser TJ, Paulus WJ, Duncker DJ, Simonides WS.Left-ventricular remodeling after myocardial infarction is associated with a cardiomyocyte-specific hypothyroid condition. Endocrinology. 2011; 152:669-679.
Simonides WS, Mulcahey MA, Redout EM, Muller A, Zuidwijk MJ, Visser TJ, Wassen FW, Crescenzi A, da-Silva WS, Harney J, Engel FB, Obregon MJ, Larsen PR, Bianco AC, Huang SA. Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic desease in rats. J Clin Invest. 2008; 118:975-983.
ONGOING RESEACH PROJECTS
Cardiac-specific activation of type III deiodinase following myocardial infarction: a therapeutic target?
The role of differential expression of deiodinases in skeletal muscle development and disease.