J Biol Chem. 2006 May 22; [Epub
ahead of print] Clin Endocrinol (Oxf). 2006 Jun;64(6):611-6.
Thyroid hormone stimulates protein synthesis in
the cardiomyocyte by activating the Akt-mTOR and p70S6K pathways.
Kenessey A, Ojamaa K.
The Feinstein Institute for Medical Research,
Thyroid hormones affect cardiac growth and phenotype; however, the
mechanisms by which the hormones induce cardiomyocyte
hypertrophy remain uncharacterized. Tri-iodo-L-thyronine
(T3) treatment of cultured cardiomyocytes for 24
hrs resulted in a 41+/-5% (p<0.001) increase in [(3)H]-leucine incorporation into total cellular protein. This
response was abrogated by the phosphatidyl-inositol
3-kinase (PI3K) inhibitor, wortmannin. Co-immunoprecipitation studies showed a direct interaction
of cytosol-localized thyroid hormone receptor,
TRalpha1, and the p85alpha subunit of PI3K. T3 treatment rapidly increased
PI3K activity by 52+/-3% (p<0.005), which resulted in increased phosphorylation of downstream kinases,
Akt and mammalian target of rapamycin
(mTOR). This effect was abrogated by
pre-treatment with wortmannin or LY294002 (LY). Phosphorylation of p70(S6K), a
known target of mTOR, occurred rapidly following
T3 treatment and was inhibited by rapamycin and wortmannin. In contrast, phosphorylation
of the p85 variant of S6K in response to T3 was not blocked by LY, wortmannin or rapamycin, thus
supporting a T3-activated pathway independent of PI3K and mTOR. 40S ribosomal protein S6, a target of p70(S6K), and 4E-BP1, a target of mTOR,
were both phosphorylated within 15-25 min. of T3
treatment and could be inhibited by wortmannin
and rapamycin. Thus, rapid T3-mediated activation
of PI3K by cytosolic TRalpha1, and subsequent
activation of the Akt-mTOR-S6K signaling pathways may underlie one of the
mechanisms by which thyroid hormone regulates physiological cardiac growth.
PMID: 16717100 [PubMed - as supplied by
publisher]
Hyperthyroidism is characterized by both increased
sympathetic and decreased vagal modulation of
heart rate: evidence from spectral analysis of heart rate variability.
Chen JL, Chiu
HW, Tseng
YJ, Chu WC.
Division of Endocrinology and Metabolism, Department of
Medicine,
Summary Objective The clinical manifestations of
hyperthyroidism resemble those of the hyperadrenergic
state. This study was designed to evaluate the impact of hyperthyroidism on
the autonomic nervous system (ANS) and to investigate the relationship
between serum thyroid hormone concentrations and parameters of spectral
heart rate variability (HRV) analysis in hyperthyroidism. Design and
patients Thirty-two hyperthyroid Graves' disease patients (mean age 31
years) and 32 sex-, age-, and body mass index (BMI)-matched normal control
subjects were recruited to receive one-channel electrocardiogram (ECG)
recording. Measurements The cardiac autonomic
nervous function was evaluated by the spectral analysis of HRV, which
indicates the autonomic modulation of the sinus node. The correlation
coefficients between serum thyroid hormone concentrations and parameters of
the spectral HRV analysis were also computed. Results The hyperthyroid
patients revealed significant differences (P < 0.001) compared with the
controls in the following HRV parameters: a decrease in total power (TP),
very low frequency power (VLF), low frequency power (LF), high frequency
power (HF), and HF in normalized units (HF%); and an increase in LF in
normalized units (LF%) and in the ratio of LF to HF (LF/HF). After
correction of hyperthyroidism in 28 patients, all of the above parameters
were restored to levels comparable to those of the controls. In addition,
serum thyroid hormone concentrations showed significant correlations with
spectral HRV parameters. Conclusions Hyperthyroidism is in a sympathovagal imbalanced state, characterized by both
increased sympathetic and decreased vagal
modulation of the heart rate. These autonomic dysfunctions can be detected
simultaneously by spectral analysis of HRV, and the spectral HRV parameters
could reflect the disease severity in hyperthyroid patients.
PMID: 16712661 [PubMed - in process]
P70S6k pathways