Brief reviewA Novel Role for Serotonin in Heart☆
Section snippets
Role of 5-HT in Embryonic Development
Both 5-HT and its receptors are expressed during early embryogenesis, suggesting that early embryos use 5-HT prior to the onset of neurogenesis to regulate cell proliferation and/or morphogenetic movements (Lauder 1993). The limiting enzyme in 5-HT biosynthesis, tryptophan hydroxylase, cannot be detected in mouse embryos between 8–10 days postcoitum (d.p.c.). Moreover, 5-HT is detected in mammalian embryonic development before tissue differentiation, indicating its maternal origin (Yavarone et
Role of 5-HT2BR in Myocardial Trabeculation
We have created 5-HT2BR gene knockout (KO) mice to address the roles of 5-HT2BR during development and in the adult. Genetic ablation of 5-HT2BR in mice induces trabeculation defects in the heart, causing lethality with variable penetrancy at mid-gestation (Nebigil et al. 2000a). KO mice exhibit two periods of lethality: one before 11.5 d.p.c., and the other right after birth. Histological analysis of hearts from 5-HT2BR KO embryos revealed defects in the subepicardial layer and a lack of
5-HT2BR Specifically Regulates ErbB-2 Receptor Expression and Signaling for Trabeculation of Heart
Mice lacking neuregulin or its receptors, ErbB-2 (HER-2/neu) and ErbB-4, show clear defects in embryonic heart development (Lemke 1996). Both ErbB-2 and ErbB-4 KO mice have ventricular trabeculation defects identical to the most severely affected 5-HT2BR KO embryos, causing death at 10.5 d.p.c. The expression patterns of 5-HT2BR, ErbB-2 and ErbB-4 overlap in the myocardium (Lee et al. 1995), whereas neuregulin is expressed in the endocardium. At 9.5 d.p.c., ErbB-2 RNA and protein expression are
5-HT2BR Mutation Alters Cardiomyocyte Function and Structure
Newborn 5-HT2BR KO mice developed cardiac dilation at a 100% penetrancy. 5-HT2BR KO neonate death resulted from inadequate cardiac output due to hypoplasia of the left ventricle, despite no evidence of pulmonary edema. The thinning of the ventricular wall and the reduction in ventricular mass observed in the 5-HT2BR KO mice are caused by two complementary mechanisms: loss of myocardial cells, and decrease in cell size. The primary loss of myocardial cells appears to be due to impaired
The 5-HT2BR KO Mice Phenotype Has Similarity with the Natural History of Patients with Dilated Cardiomyopathy
Dilated cardiomyopathy in humans is diagnosed with two typical features, left ventricular (LV) dilatation, and depressed LV systolic performance. These features are also observed in adult 5-HT2BR KO mouse hearts. All 5-HT2BR KO mice surviving until the first postnatal week developed to adulthood with dilated cardiomyopathy-like symptoms. Echographic analysis showed that LV end-diastolic diameter (LVEDD) and the LV end-systolic diameter (LVESD) were significantly increased in male 5-HT2BR KO
Is the 5-HT2BR Involved in the Etiology of Drug-Induced Cardiopathy?
The mitogenic action of 5-HT via 5-HT2BR has been proposed to trigger the valvular hyperplasia observed in carcinoid patients (Robiolio et al. 1995). Some patients taking appetite suppressants, such as norfenfluramine or ergot derivatives, which have been recently identified as 5-HT2BR-specific agonists, also experience valvular hyperplasia Fitzgerald et al. 2000, Porter et al. 1999, Rothman et al. 2000. However, the lack of detectable valvular defects in 5-HT2BR KO mice indicates that the 5-HT
Future Directions
Several studies of cultured cardiomyocytes and transgenic mouse models showed that neurohumoral and hemodynamic factors are involved in development of cardiomyopathy. Neurohumoral factors, which use Gq-coupled receptors, have been widely studied (McKinsey and Olson 1999). In isolated neonatal cardiomyocytes, Gq-coupled receptor agonists such as norepinephrine, angiotensin II, endothelin-1, thrombin, lysophosphatidic acid, and prostaglandin induce hypertrophy (Adams and Brown 2001). Transgenic
Acknowledgements
The excellent drawings of Dr. Laurent Désaubry are greatly appreciated. We thank Drs. K. Niederreither and S. Tan for critical reading of the manuscript and for helpful discussions.
This work has been supported by funds from the Centre National de la Recherche Scientifique, the Institut National de la Santé et de la Recherche Médicale, the Hôpital Universitaire de Strasbourg, the Université Louis Pasteur, and by grants from the Fondation de France, the Fondation pour la Recherche Médicale, the
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2018, European Journal of PharmacologyCitation Excerpt :5-HT affects the cardiovascular system both directly through heart and peripheral vasculature, and/or indirectly through the CNS (Mago et al., 2014). 5-HT acts on the vagus and sympathetic nerves (Nebigil, 2001), eliciting bradycardia by Bezold-Jarisch reflex and sympatholytic action by inhibiting NA release (Watts et al., 2012). In the CNS, 5-HT induces contradictory actions depending on activation of receptor subtypes (Lewis and Coote, 1990; Nalivaiko and Sgoifo, 2009), i.e., a decrease in sympathetic activity and an increase in parasympathetic activity via 5-HT1A receptors (Nalivaiko and Sgoifo, 2009; Ramage, 2001), while an increase in arterial pressure via 5-HT2A receptors (Nalivaiko and Sgoifo, 2009; Ramage and Daly, 1998).
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