Aufklärung der Wirkung von Thyronaminen bei der Thermoregulation und Herz-Kreislauf-Funktion
Zusammenfassung der Projektergebnisse
Thyroid hormone is one of the key players in modulating cardiovascular function, blood pressure and body temperature. Thyronamines are decarboxylated thyroid hormone metabolites linking endocrinology, cardiovascular function and metabolism. A single injection of 3-iodothyronamine (3-T1AM) led to rapid and coordinated major decreases in body temperature and heart rate. Several risk factors such as thyroid dysfunction and hypertonia have been identified to predispose to cardiovascular disorders; however, the underlying molecular mechanisms behind the hypothermia and bradycardia induced by 3-T1AM are still not completely understood. In contrast to the acute effects of 3-T1AM, we could not detect a significant change in heart rate, blood pressure, body and brown fat temperature after repeated administration of pharmacological 3-T1AM doses in mice. Although 3-T1AM is rapidly converted to several other metabolites in vivo, these strong and rapid pharmacological responses on cardiovascular function and thermoregulation were solely attributed to 3-T1AM, leaving potential contributions of downstream products untested. Here, our in vivo data conclusively demonstrate that 3-iodothyroacetic acid, the main degradation product of 3-T1AM, does not contribute to the cardiovascular or thermoregulatory effects observed after 3-T1AM administration, suggesting that the oxidative deamination constitutes an important deactivation mechanism for 3-T1AM. The lack of hypothermia and bradycardia clearly indicates that the amino group in the ethylamine side chain is indispensable for the rapid effects of 3-T1AM. However, this project lead to the discovery of an entirely novel hormone called N-acetyl-3-iodothyronamine (NAc-3-T1AM), which is produced by liver and white fat from 3-T1AM, and increases heart rate and blood pressure by activating α-adrenergic signaling on cardiomyocytes, constituting a previously unknown molecular link between thyroid hormone signaling and the autonomic nervous system.
Projektbezogene Publikationen (Auswahl)
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3- Iodothyroacetic acid lacks thermoregulatory and cardiovascular effects in vivo. Br J Pharmacol. 2015 Jul;172(13):3426-33
Hoefig CS, Jacobi SF, Warner A, Harder L, Schanze N, Vennström B, Mittag J
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3-iodothyronamine differentially modulates α-2A-adrenergic receptormediated signaling. J Mol Endocrinol. 2015 Jun;54(3):205-16
Dinter J, Mühlhaus J, Jacobi SF, Wienchol CL, Cöster M, Meister J, Hoefig CS, Müller A, Köhrle J, Grüters A, Krude H, Mittag J, Schöneberg T, Kleinau G, Biebermann H
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Biosynthesis of 3-Iodothyronamine From T4 in Murine Intestinal Tissue. Endocrinology. 2015 Nov;156(11):4356-64
Hoefig CS, Wuensch T, Rijntjes E, Lehmphul I, Daniel H, Schweizer U, Mittag J, Köhrle J
