Chronic Cardiac-Specific Thyrotoxicosis Increases Myocardial β-Adrenergic Responsiveness

Abstract

Whereas many cardiac symptoms of thyrotoxicosis resemble those of the hyperadrenergic state, circulating catecholamines are reduced or normal in this condition. To test the hypothesis that the thyrotoxic heart is hypersensitive to catechol-amines, we studied beta-adrenergic signaling in a transgenic (TG) mouse in which the human type 2 iodothyronine deiodinase (D2) gene is expressed in myocardium. Because D2 converts T4 to T3, the active form of thyroid hormone, the D2 TG mouse exhibits mild, chronic thyrotoxicosis that is limited to the myocardium. In the current study, we determined that cAMP accumulation in response to either norepinephrine or forskolin treatment was increased in isolated ventricular myocardiocytes and membrane-enriched fractions prepared from these D2 TG hearts as compared with wild type. This increase in adenylyl cyclase (AC) Vmax could not be explained by changes in AC isoform expression or changes in the long or short forms of stimulatory G-protein Gsalpha, which were approximately 10% decreased in D2 TG membranes. However, Western analysis and ADP-ribosylation studies suggest that the increase in AC Vmax is mediated by a decrease in the expression of inhibitory G proteins (Gialpha-3 and/or Goalpha). These data suggest that cardiac thyrotoxicosis leads to increased beta-adrenergic responsiveness of cardiomyocytes via alterations in the regulatory G-protein elements of the AC membrane complex.

The Small Polyphenolic Molecule Kaempferol Increases Cellular Energy Expenditure and Thyroid Hormone Activation

“…Biochemical assays Cyclic AMP measurement. The cyclic AMP (cAMP) content of MSTO-211H cells was measured using an [ 125 I]cAMP commercial radioimmunoassay kit (NEK-033; Perkin Elmer, Shelton, CT) according to the manufacturer's instructions and previously described methods (15). Deiodinase activity.…”

Nongenomic signaling pathways triggered by thyroid hormones and their metabolite 3‐iodothyronamine on the cardiovascular system

“…It may be responsible, at least in part, for the enhanced catecholamine sensitivity of b1R-coupled cardiac responses in the hyperthyroidism state (Williams et al, 1977;Tse et al, 1980). Decreased levels of Gi in ventricular cells exposed to T 3 may also contribute to the increased b-adrenergic sensitivity (Carvalho-Bianco et al, 2004).…”

Activation and inactivation of thyroid hormone by deiodinases: Local action with general consequences

“…The human heart expresses high levels of D2 mRNA in contrast to the low D2 levels in the rodent heart [11,92]. Transgenic mice overexpressing D2 in the myocardium have mild chronic cardiac thyrotoxicosis [132] associated with increased b-adrenergic responsiveness of cardiomyocytes [133,134]. It has been demonstrated that Nkx-2.5 and GATA-4 interact with the TTF-1 binding sites of the human dio2 5'FR and induce D2 expression while the absence of these binding sites results in a lower D2 mRNA level in the rat heart [90].…”