Maladaptive cardiac hypertrophy results in phenotypic changes in several genes 
that are thyroid hormone responsive, suggesting that thyroid hormone receptor 
(TR) function may be altered by cellular kinases, including protein kinase C 
(PKC) isozymes that are activated in pathological hypertrophy. To investigate 
the role of PKC signaling in regulating TR function, cultured neonatal rat 
ventricular myocytes were transduced with adenovirus (Ad) expressing wild-type 
(wt) or kinase-inactive (dn) PKC alpha or constitutively active (ca) PKC delta 
and PKC epsilon. Overexpression of wtPKC alpha, but not caPKC delta or caPKC 
epsilon, induced a 28-fold increase (P < 0.001) in TR alpha1 protein in the 
nuclear compartment and a smaller increase in the cytosol. Furthermore, TR 
alpha1 mRNA was increased 55-fold (P < 0.001). This effect of PKC alpha was 
dependent on its kinase activity because dnPKC alpha was without effect. Phorbol 
12-myristate 13-acetate (PMA) induced nuclear translocation of endogenous PKC 
alpha and Ad-wtPKC alpha concomitantly with an increase in nuclear TR alpha1 
protein. In contrast, PMA-induced nuclear translocation of dnPKC alpha resulted 
in a decrease of TR alpha1. The increase in TR alpha1 protein in Ad-wtPKC 
alpha-transduced cardiomyocytes was not the result of a reduced rate of protein 
degradation, nor was the half-life of TR alpha1 mRNA prolonged, suggesting a PKC 
alpha-mediated effect on TR alpha transcription. Although phosphorylation of 
ERK1/2 was increased in Ad-wtPKC alpha-transduced cells, inhibition of 
phospho-ERK did not change TR alpha1 expression. PKC alpha overexpression in 
cardiomyocytes caused marked repression of triiodothyronine (T3)-responsive 
genes, alpha-myosin heavy chain, and the sarcoplasmic reticulum 
calcium-activated adenosinetriphosphatase SERCA2. Treatment with T3 for 4 h 
resulted in significant reductions of PKC alpha in nuclear and cytosolic 
compartments, and decreased TR alpha1 mRNA and protein, with normalization of 
phenotype. These results implicate PKC alpha as a regulator of TR function and 
suggest that nuclear localization of PKC alpha may control transcription of the 
TR alpha gene, and consequently, affect cardiac phenotype.