TNF-α Administration in Neonatal Cardiomyocytes is Associated with Differential Expression of Thyroid Hormone Receptors: A Response Prevented by T₃

Introduction

Although it has long been recognized that several genes encoding important regulatory and structural proteins in the myocardium (related to function, metabolism, and response to stress) are thyroid hormone responsive, the role of thyroid hormone in cardiac diseases remains largely unknown [1] [2]. Recent research provides substantial evidence showing that changes in thyroid hormone signaling can occur in cardiac hypertrophy and in heart failure and low thyroid hormone levels in plasma appear to be an independent risk factor for increased mortality and morbidity in heart failure patients [3] [4]. Furthermore, the expression of thyroid hormone nuclear receptors in the myocardium is also altered during cardiac remodeling following acute myocardial infarction [5] [6]. Interestingly, a differential pattern of thyroid hormone receptors (TRs) expression in the viable rat myocardium has been observed after myocardial infarction; TRβ1 is downregulated while TRα1 is overexpressed and circulating T₃ (triiodothyronine) in blood is decreased [6]. Thus, TRα1 is in unliganded state and functions as apo-receptor; its repressive activity predominates with depression of the expression of important contractile proteins as this occurs in fetal life [7] [8]. It is of note that overexpression of TRα1 in cells promotes cell growth and induces a fetal like pattern of myosin expression, while overexpression of TRβ1 receptor has the opposite effect [9]. Although these observations seem to be of important physiological relevance, the underlying mechanisms of this response remain largely unknown. Neuro-hormonal changes and the inflammatory response, which both are implicated in cardiac remodeling, may play a role. Thus, we have previously demonstrated that an interaction can occur between the α1-adrenergic and the thyroid hormone signaling at the level of thyroid hormone nuclear receptors [6]. In the present study, we further investigated whether TNF-α could also be involved in the regulation of thyroid hormone receptors in cultured cardiomyocytes. The proinflammatory response plays a critical role in cardiac remodeling, and cytokines, such as TNF-α, are closely associated with cardiac dysfunction in animals and patients with heart failure [10], while therapies targeting TNF-α signaling are now considered as potential treatment in patients with heart failure [11] [12].

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