Pressure overload-induced cardiac hypertrophy results in a pathological type of 
hypertrophy with activation of signaling cascades like the extracellular 
signal-regulated kinase (ERK) pathway, which promotes negative cardiac 
remodeling and decreased contractile function. In contrast, thyroid hormone 
mediates a physiological type of hypertrophy resulting in enhanced contractile 
function. In addition, thyroid hormone action is diminished in pressure 
overload-induced cardiac hypertrophy. We hypothesized that thyroid hormone 
status modulates ERK activity and that administration of thyroid hormone could 
alter the activity of this kinase in cardiac hypertrophy induced by pressure 
overload. ERK is activated by phosphorylation; accordingly, we investigated 
phosphorylation of ERK in hearts of control, hypothyroid, and hyperthyroid mice. 
In addition, the effect of T3 treatment on ERK phosphorylation in hypertrophied 
hearts from transverse aortic-constricted (TAC) mice was investigated. Results 
showed that phosphorylated ERK (p-ERK) was decreased by 25% in hyperthyroid 
mice. In contrast, hypothyroid mice presented increased p-ERK by 80%. TAC mice 
presented a greater than fourfold increase of p-ERK compared with control mice. 
Interestingly, T3 administration dramatically canceled TAC-induced ERK 
phosphorylation (36% lower compared with control). Raf-1 is upstream of the ERK 
pathway. TAC mice presented a 45% increase in phospho-Raf-1 (Ser338). T3 
treatment inhibited this effect of pressure overload and further decreased 
p-Raf-1 (Ser338) by 37%, compared with control. Overexpression of thyroid 
hormone receptor-α in cultured cardiomyocytes potentiated the inhibitory effect 
of T3 on ERK phosphorylation. We concluded that thyroid hormone has an 
inhibitory effect on the Raf-1/ERK pathway. Furthermore, treatment of TAC mice 
with T3 inhibited Raf-1/ERK pathway by a thyroid hormone receptor-dependent 
mechanism.