Thyroid hormone (TH) and TH receptors (TRs) α and β act by binding to TH response elements (TREs) in regulatory regions of target genes. This nuclear signaling is established as the canonical or type 1 pathway for TH action. Nevertheless, TRs also rapidly activate intracellular second-messenger signaling pathways independently of gene expression (noncanonical or type 3 TR signaling). To test the physiological relevance of noncanonical TR signaling, we generated knockin mice with a mutation in the TR DNA-binding domain that abrogates binding to DNA and leads to complete loss of canonical TH action. We show that several important physiological TH effects are preserved despite the disruption of DNA binding of TRα and TRβ, most notably heart rate, body temperature, blood glucose, and triglyceride concentration, all of which were regulated by noncanonical TR signaling. Additionally, we confirm that TRE-binding-defective TRβ leads to disruption of the hypothalamic-pituitary-thyroid axis with resistance to TH, while mutation of TRα causes a severe delay in skeletal development, thus demonstrating tissue- and TR isoform-specific canonical signaling. These findings provide in vivo evidence that noncanonical TR signaling exerts physiologically important cardiometabolic effects that are distinct from canonical actions. These data challenge the current paradigm that in vivo physiological TH action is mediated exclusively via regulation of gene transcription at the nuclear level.

Purpose: Thyroid hormones (TH) play a central role for cardiac function. TH influence heart rate and cardiac contractility, and altered thyroid function is associated with increased cardiovascular morbidity and mortality. The precise role of TH in onset and progression of heart failure still requires clarification.Methods: Chronic left ventricular pressure overload was induced in mouse hearts by transverse aortic constriction (TAC). One week after TAC, alteration of TH status was induced and the impact on cardiac disease progression was studied longitudinally over 4 weeks in mice with hypo- or hyperthyroidism and was compared to euthyroid TAC controls. Serial assessment was performed for heart function (2D M-mode echocardiography), heart morphology (weight, fibrosis, and cardiomyocyte cross-sectional area), and molecular changes in heart tissues (TH target gene expression, apoptosis, and mTOR activation) at 2 and 4 weeks.Results: In diseased heart, subsequent TH restriction stopped progression of maladaptive cardiac hypertrophy and improved cardiac function. In contrast and compared to euthyroid TAC controls, increased TH availability after TAC propelled maladaptive cardiac growth and development of heart failure. This was accompanied by a rise in cardiomyocyte apoptosis and mTOR pathway activation.Conclusion: This study shows, for the first time, a protective effect of TH deprivation against progression of pathological cardiac hypertrophy and development of congestive heart failure in mice with left ventricular pressure overload. Whether this also applies to the human situation needs to be determined in clinical studies and would infer a critical re-thinking of management of TH status in patients with hypertensive heart disease.

Background Hypothyroidism impairs cardiovascular health and contributes to endothelial dysfunction with reduced vasodilation. How triiodothyronine (T3) and its receptors are involved in the regulation of vasomotion is not yet fully understood. In general, thyroid hormone receptors (TRs) either influence gene expression (canonical action) or rapidly activate intracellular signaling pathways (noncanonical action). Here we aimed to characterize the T3 action underlying the mechanism of arterial vasodilation and blood pressure regulation. Methods Mesenteric arteries were isolated from male rats, wildtype (WT) mice, TRα knockout (TRα 0) mice and from knock-in mice with a mutation in the DNA-binding domain (TRα GS). In this mutant, DNA-binding and, thus, canonical action is abrogated while noncanonical signaling is preserved. In a wire myograph system, the isolated vessels were pre-constricted with norepinephrine. The response to T3 was measured, and the resulting vasodilation (Δ force [mN]) was normalized to maximum contraction with norepinephrine and expressed as percent vasodilation after maximal pre-constriction with norepinephrine (% NE). Isolated vessels were treated with T3 (1x10 -15 to 1x10 -5 mol/L) alone and in combination with the endothelial NO-synthase (eNOS) inhibitor L-NG-Nitroarginine methyl ester (L-NAME) or the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin. The endothelium was removed to determine the contribution of T3 to endothelium-dependent vasodilation. The physiological relevance of T3-induced vasodilation was determined by in vivo arterial blood pressure measurements in male and female mice. Results T3 treatment induced vasodilation of mesenteric arteries from WT mice within 2 minutes (by 21.5±1.7% NE). This effect was absent in arteries from TRα 0 mice (by 5.3±0.6% NE, P<0.0001 vs. WT) but preserved in TRαGS arteries (by 17.2±1.1% NE, n.s. vs. WT). Inhibition of either eNOS or PI3K reduced T3-mediated vasodilation from 52.7±4.5% NE to 28.5±4.1% NE and 22.7±2.9% NE, respectively. Removal of the endothelium abolished the T3-mediated vasodilation in rat mesenteric arteries (by 36.7±5.4% NE vs. 3.5±6.2% NE). In vivo, T3 injection led to a rapid decrease of arterial blood pressure in WT (by 13.9±1.9 mmHg) and TRαGS mice (by 12.4±1.9 mmHg), but not in TRα0 mice (by 4.1±1.9 mmHg). Conclusions These results demonstrate that T3 acting through noncanonical TRa action impacts cardiovascular physiology by inducing endothelium-dependent vasodilation within minutes via PI3K and eNOS activation.

Age and sex impact prevalence and clinical features of thyroid disease. Thyroid dysfunction occurs with a higher frequency in elderly patients and females. Moreover, age alters clinical presentation of hyper- and hypothyroidism and onset of thyroid hormone (TH) related co-morbidities leading to increased risk for underdiagnosis and maltreatment in the elderly. Rodent models allow further insights into mechanisms of age- and sex-dependent TH action in target tissues. In this review, we summarize findings from mouse studies showing distinct effects of age and sex on systemic versus organ-specific TH action and discuss their wider implication for clinical care.

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