Thyroid Hormone Stimulates Protein Synthesis in the Cardiomyocyte by Activating the Akt-mTOR and p70S6K Pathways

Abstract

Thyroid hormones affect cardiac growth and phenotype; however, the mechanisms by which the hormones induce cardiomyocyte hypertrophy remain uncharacterized. Tri-iodo-Lthyronine (T3) treatment of cultured cardiomyocytes for 24 h resulted in a 41 ؎ 5% ( p < 0.001) increase in [ 3 H]leucine incorporation into total cellular protein. This response was abrogated by the phosphatidylinositol 3-kinase (PI3K) inhibitor, wortmannin. Co-immunoprecipitation studies showed a direct interaction of cytosol-localized thyroid hormone receptor TR␣1 and the p85␣ 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 pretreatment with wortmannin or LY294002. 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 LY294002, wortmannin, or rapamycin, thus supporting a T3-activated pathway independent of PI3K and mTOR. 40 S 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 TR␣1 and subsequent activation of the Akt-mTOR-S6K signaling pathway may underlie one of the mechanisms by which thyroid hormone regulates physiological cardiac growth.The observation that thyroid hormone treatment of patients and experimental animal models of heart failure can improve cardiac function has been attributed in part to its regulation of cardiac genes (1-5). It has also been well documented that thyroid hormones stimulate physiologic cardiac hypertrophy (6); however, the intracellular mechanisms underlying this response remain poorly defined. Patients with chronic hyperthyroidism experience a marked reduction in systemic vascular resistance with increased cardiac contractility and cardiac output, often associated with ventricular hypertrophy (7,8). However, the role of thyroid hormones on gene expression fails to satisfactorily explain the effects observed on cardiomyocyte growth. Recent published studies supporting the cytosolic localization and non-transcriptional activities of thyroid hormone receptors may underlie thyroid hormone-induced physiological growth (9 -11). Evidence of protein-protein interactions between cytosolic thyroid hormone receptors and the p85␣ regulatory subunit of phosphatidylinositol 3-kinase (PI3K), 2 and activation of PI3K activity by T3 treatment have been reported (12, 13). Activation of the PI3K␣-Akt-mTOR pathway by IGF-1 and transgenic animal models expressing molecular components of this pathway have implicated the PI3K-Akt signaling pathway in determining heart size and physiologic cardiac growth (14 -18). Recently, Kuzman et al. (19) reported that the Akt-mTOR signaling pathway was activa...

The role of thyroid hormone receptor DNA binding in negative thyroid hormone-mediated gene transcription

“…Since the overall structure of this DBD mutant remains unaffected (Shibusawa et al 2003a), it is likely that a suggested protein-protein interaction domain remains intact. As also suggested for different members of the nuclear receptor family, these proteins are targets of post-translational modifications, which facilitate their function within the transrepression mechanism (Moeller et al 2005, Hiroi et al 2006, Kenessey & Ojamaa 2006, Storey et al 2006, Wulf et al 2007. Further investigations should target these questions with special emphasis on the DBD of TR.…”

Thyroid hormone inhibits biliary growth in bile duct-ligated rats by PLC/IP3/Ca2+-dependent downregulation of SRC/ERK1/2

“…Indeed, thyroid hormone acts on the plasma membrane by membrane-associated THRs regulating ion channels, ion pump activities, certain cytoplasmic proteins, at the ribosome and Golgi apparatus, and upon the cytoskeleton (6,21). Both TR␣ and TR␤ can localize in the cytoplasm (28), where they mediate T3 rapid effects through extranuclear pathways (28) involving mitogen-activated protein kinase, Src, and IP3-kinase (32).…”

Nicotinic Acetylcholine Receptor-Mediated Protection of the Rat Heart Exposed to Ischemia Reperfusion

“…Hearts of 2-d-old rat pups (Sprague-Dawley) were digested with collagenase to isolate ventricular myocytes as previously published (21). Experiments were repeated on a second independent isolation of primary ventricular myocytes to verify the results obtained.…”