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

Abstract

Thyroid hormones play a wide range of important physiological activities in almost all organism. As changes in these hormones levels-observed in hypothyroidism and hyperthyroidism-promote serious derangements of the cardiovascular system, it is important to know their mechanisms of action. Although the classic genomic actions which are dependent on interaction with nuclear receptors to modulate cardiac myocytes genes expression, there is growing evidence about T(3) and T(4)-triggered nongenomic pathways, resulted from their binding to plasma membrane, cytoplasm, or mitocondrial receptors that leads to a rapidly regulation of cardiac functions. Interestingly both actions converge to amplify thyroid hormone effects on cardiovascular system. T(3) and T(4) nongenomic actions modify inotropic and chronotropic effects, cardiac action potential duration, cardiac growth, and myocyte shape by protein translation through protein kinases-dependent signaling cascades, which include PKA, PKC, PI3K, and MAPK, and changes on ion channels and pumps activity. In respect to the decreased systemic vascular resistance seen in hyperthyroidism, T(3) appears to activate NOS or ATP-sensitive K(+) channels. In addition, a novel biologically active T(4)-derived metabolite has been described, 3-iodothyronamine, T(1)AM, which also acts through membrane receptors to mediate nongenomic cardiac effects. This metabolite influences the physiological manifestations of thyroid hormone actions by inducing opposite effects from those stimulated by T(3) and T(4), such as negative inotropic and chronotropic effects. Therefore, beyond genomic and nongenomic effects of thyroid hormones, it is crucial for there to be an equilibrium between T(3) or T(4) and T(1)AM levels for maintaining cardiac homeostasis.

The Impact of a Non-Functional Thyroid Receptor Beta upon Triiodotironine-Induced Cardiac Hypertrophy in Mice

“…Moreover, T3 can bind to plasma membrane thyroid receptors, such as integrin α V β 3 [3,4], activating quick-start signalling cascades, including phosphatidylinositol 3'-kinase (PI3K) and mitogen-activated protein kinase (MAPK) [5], which can regulate ribosomal biogenesis and protein translation and modulate the activity of membrane ions transporters, among other actions [6]. Additionally, non-genomic TH activation can interact with the genomic effects and contribute towards an overall effect on the heart [7,8].…”

Long-Term Neurodevelopmental Outcome of Children Treated with Tri-Iodothyronine after Cardiac Surgery: Follow-Up of a Double-Blind, Randomized, Placebo-Controlled Study

“…The nongenomic mechanisms are immediate and occur mostly at the cell membrane. For example, they include rapid T3-mediated stimulation of Na + influx, which indirectly increases intracellular Ca 2+ via Na + -Ca 2+ exchange, leading to positive inotropic effects [21]. However, the genomic thyroid hormone mechanisms involve T4 and T3 transport across cell membranes, intracellular enzyme-mediated deiodination of T4 to T3, binding to thyroid nuclear receptors, and modulation of transcription and protein translation, altogether rather time-consuming processes [21].…”

“…For example, they include rapid T3-mediated stimulation of Na + influx, which indirectly increases intracellular Ca 2+ via Na + -Ca 2+ exchange, leading to positive inotropic effects [21]. However, the genomic thyroid hormone mechanisms involve T4 and T3 transport across cell membranes, intracellular enzyme-mediated deiodination of T4 to T3, binding to thyroid nuclear receptors, and modulation of transcription and protein translation, altogether rather time-consuming processes [21]. Portman et al [19], who reported that T3 supplementation provided clinical advantages only in children younger than 5 months undergoing a CPB operation, also postulated a predominance of nongenomic actions relative to the genomic actions to explain their results.…”

Hypothyroidism Modifies Lipid Composition of Polymorphonuclear Leukocytes

“…Many facets of PMNs activation depend directly on Ca 2+ entry into the cell [65], thus the Cell Physiol Biochem 2012;29:713-724 cellular cholesterol deficiency could limit inflammatory responses and regulate the immune cell activity. Recently, non-genomic actions of thyroid hormones have been described [66]. Some functions of PMNs, including generation of reactive oxygen species (ROS), are affected by hypothyroidism and are mediated by a membrane-bound receptor for thyroid hormones [67,68].…”