alpha(1)-adrenergic stimulation inhibits 3,5,3'-triiodothyronine-induced expression of the rat heart sarcoplasmic reticulum Ca2+ adenosine triphosphatase gene

The interactions between the beta-adrenergic system and thyroid hormone (T-3) on cardiac function have been investigated in detail. In addition to beta-adrenoreceptors, alpha(1)-adrenergic receptors are present in the mammalian heart. The interactions T-3 and the alpha(1)-adrenergic system remain, however, poorly understood. T-3 stimulates the expression and transcription of the sarcoplasmic reticulum Ca2+ adenosine triphosphatase (SERCA2) gene, a protein vital in the control of cardiac calcium transients and contractility. We show that in rat cardiac myocytes, the stimulatory effect of T-3 on SERCA2 messenger RNA expression and gene transcription is inhibited by an alpha(1)-adrenergic agonist. We demonstrate that direct activation of the alpha(1)-adrenergic signaling pathway, using mutant constitutively active G protein (G(4)) similarly down-regulated the T-3 effect on SERCA2 transcription. The combined effect of the thyroid hormone receptor and retinoid X receptors on T-3-stimulated SERCA2 gene transcription was also markedly attenuated by alpha(1)-adrenergic stimulation. These results suggested that activation of the alpha(1)-adrenergic signaling pathway has an inhibitory effect on T-3-dependent SERCA2 gene transcription. As this inhibitory effect of alpha(1)-adrenergic stimulation occurs when only one thyroid hormone response element (TRE) drives reporter expression, it is most likely mediated by an alteration of the nuclear factors binding to the TRE or by influencing the interaction of the nuclear factors binding to the TRE or by influencing the interaction of the TRE complex with the basal transcriptional machinery.