Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers.

Atrial fibrillation is the most common clinical cardiac arrhythmia. It is often initiated by ectopic beats arising from the pulmonary veins and atrium, but the source and mechanism of these beats remains unclear. The melanin synthesis enzyme dopachrome tautomerase (DCT) is involved in intracellular calcium and reactive species regulation in melanocytes. Given that dysregulation of intracellular calcium and reactive species has been described in patients with atrial fibrillation, we investigated the role of DCT in this process. Here, we characterize a unique DCT-expressing cell population within murine and human hearts that populated the pulmonary veins, atria, and atrioventricular canal. Expression profiling demonstrated that this population expressed adrenergic and muscarinic receptors and displayed transcriptional profiles distinct from dermal melanocytes. Adult mice lacking DCT displayed normal cardiac development but an increased susceptibility to atrial arrhythmias. Cultured primary cardiac melanocyte-like cells were excitable, and those lacking DCT displayed prolonged repolarization with early afterdepolarizations. Furthermore, mice with mutations in the tyrosine kinase receptor Kit lacked cardiac melanocyte-like cells and did not develop atrial arrhythmias in the absence of DCT. These data suggest that dysfunction of melanocyte-like cells in the atrium and pulmonary veins may contribute to atrial arrhythmias.

Antisense oligonucleotide targeting the transforming growth factor beta1 increases expression of specific genes and functions of Leydig cells.

Transforming growth factor beta1 (TGFbeta1) has been reported to be a potent inhibitor of differentiated functions of many steroidogenic cells. Porcine Leydig cells (LC), as well as Sertoli cells (SC), express TGFbeta1 mRNA and secrete this peptide, suggesting that it might play an autocrine role. Moreover, many studies have suggested a possible paracrine regulation of LC by SC-secreted factors. To assess whether TGFbeta1 plays an autocrine/paracrine role on these steroidogenic cells, we attempted to inhibit TGFbeta1 protein synthesis by transfecting LC, SC and LC+SC for 24 h with 10 microM of an unmodified antisense oligonucleotide (AON) complementary to the translation-initiation region of the TGFbeta1 mRNA and, as controls, with the corresponding sense (SON) or scrambled (SCRON) oligonucleotides. First, we determined at which level, transcriptional or translational, the TGFbeta1 AON acts. Neither TGFbeta1 AON, SON nor SCRON modified TGFbeta1 mRNA levels in LC, SC or LC+SC. However, TGFbeta1 AON caused the disappearance of TGFbeta1 immunoreactivity in both cell types. In addition, TGFbeta1 AON reduced the attachment of TGFbeta1 mRNA in ribosomal and polyribosomal fractions. Then, we showed that the decrease of the TGFbeta1 protein induced by the AON results in an increase of the expression of LC specific genes and of LC steroidogenic capacity. In LC and LC+SC, TGFbeta1 AON increased the mRNA levels of both LH/hCG receptor (1.9-fold and 3.5-fold, respectively) and P450 c17 (5-fold and 8-fold, respectively). This was associated with an enhancement of hCG-induced testosterone production by both LC and LC+SC (1.6-fold and 2.2-fold, respectively) when compared with untransfected cells. The TGFbeta1 AON effects were always more pronounced on LC+SC than on LC. The present findings show that TGFbeta1 has an autocrine/paracrine inhibitory effect on cultured porcine Leydig cells, an effect that can be overcome by TGFbeta1 AON.

[Physiology of the anterior pituary gland]. / Physiologie de l'antéhypophyse.

The anterior pituitary is a complex gland which controls the various peripheral endocrine glands (thyroid, adrenal cortex, ovary and testis) as well as essential functions as growth, reproduction and lactation. Its physiological role is of paramount importance and its pathology multiple, including functional dysregulations and diseases caused by lesions or tumors, in particular pituitary adenomas. Recent data show that, in addition to the classical control of anterior pituitary hormones by hypothalamic neuropeptides and by peripheral hormones, local controls of the paracrine or autocrine type exist. Although these new findings seem to increase the complexity of anterior pituirary control, they might, in the future, shed further light on the physiopathology of this gland.

[Release of thyrotropin releasing hormone (TRH) from human prolactin-secreting pituitary adenoma cells. Modulation by dopamine]. / Libération de thyrolibérine (TRH) par les cellules adénomateuses hypophysaires humaines à prolactine. Modulation par la dopamine.

We found, by radioimmunoassay, that thyrotropin-releasing-hormone (TRH) was present in human prolactin (PRL)-secreting adenomas (mean: 89 +/- 45 (SEM) fmol/mg proteins) and was released by perifused adenomatous cells at levels varying from 5 to 60 fmol/10(6) cell/2 min. TRH release was increased in the presence of dopamine (DA) 10(-6) M but was not modified by the presence of somatostatin (SRIH) 10(-6) M.