Role of Endothelial AADC in Cardiac Synthesis of Serotonin and Nitrates Accumulation

Serotonin (5-HT) regulates different cardiac functions by acting directly on cardiomyocytes, fibroblasts and endothelial cells. Today, it is widely accepted that activated platelets represent a major source of 5-HT. In contrast, a supposed production of 5-HT in the heart is still controversial. To address this issue, we investigated the expression and localization of 5-HT synthesizing enzyme tryptophan hydroxylase (TPH) and L-aromatic amino acid decarboxylase (AADC) in the heart. We also evaluated their involvement in cardiac production of 5-HT. TPH1 was weakly expressed in mouse and rat heart and appeared restricted to mast cells. Degranulation of mast cells by compound 48/80 did not modify 5-HT cardiac content in mice. Western blots and immunolabelling experiments showed an abundant expression of AADC in the mouse and rat heart and its co-localization with endothelial cells. Incubation of cardiac homogenate with the AADC substrate (5-hydroxy-L-tryptophan) 5-HTP or intraperitoneal injection of 5-HTP in mice significantly increased cardiac 5-HT. These effects were prevented by the AADC inhibitor benserazide. Finally, 5-HTP administration in mice increased phosphorylation of aortic nitric oxide synthase 3 at Ser (1177) as well as accumulation of nitrates in cardiac tissue. This suggests that the increase in 5-HT production by AADC leads to activation of endothelial and cardiac nitric oxide pathway. These data show that endothelial AADC plays an important role in cardiac synthesis of 5-HT and possibly in 5-HT-dependent regulation of nitric oxide generation.

[1]  J. Liao,et al.  Oxidized Low‐Density Lipoprotein Inhibits Nitric Oxide‐Mediated Coronary Arteriolar Dilation by Up‐regulating Endothelial Arginase I , 2011, Microcirculation.

[2]  J. Hernández-Rodríguez,et al.  Characterization of serotonergic cells in fetal heart tissue. , 2009, Cirugia y cirujanos.

[3]  A. Caudrillier,et al.  Dose-dependent activation of distinct hypertrophic pathways by serotonin in cardiac cells. , 2009, American journal of physiology. Heart and circulatory physiology.

[4]  Ji-Fu Wei,et al.  Induction of mast cell accumulation, histamine release and skin edema by N49 phospholipase A2 , 2009, BMC Immunology.

[5]  J. Mialet-Perez,et al.  Platelet derived serotonin drives the activation of rat cardiac fibroblasts by 5-HT2A receptors. , 2009, Journal of molecular and cellular cardiology.

[6]  I. Sora,et al.  Depletion of serotonin and selective inhibition of 2B receptor suppressed tumor angiogenesis by inhibiting endothelial nitric oxide synthase and extracellular signal-regulated kinase 1/2 phosphorylation. , 2009, Neoplasia.

[7]  S. Watts.  The love of a lifetime: 5-HT in the cardiovascular system. , 2009, American journal of physiology. Regulatory, integrative and comparative physiology.

[8]  S. Watts,et al.  The existence of a local 5‐hydroxytryptaminergic system in peripheral arteries , 2008, British journal of pharmacology.

[9]  M. Hamon,et al.  Tryptophan hydroxylase 1 knockout and tryptophan hydroxylase 2 polymorphism: effects on hypoxic pulmonary hypertension in mice. , 2007, American journal of physiology. Lung cellular and molecular physiology.

[10]  C. Villalón,et al.  Cardiovascular responses produced by 5-hydroxytriptamine:a pharmacological update on the receptors/mechanisms involved and therapeutic implications , 2007, Naunyn-Schmiedeberg's Archives of Pharmacology.

[11]  D. Power,et al.  Regulation of endothelial and myocardial NO synthesis by multi-site eNOS phosphorylation. , 2007, Journal of molecular and cellular cardiology.

[12]  M. Humbert,et al.  Cross talk between endothelial and smooth muscle cells in pulmonary hypertension: critical role for serotonin-induced smooth muscle hyperplasia. , 2006, Circulation.

[13]  F. Levy,et al.  5-hydroxytryptamine receptors in the human cardiovascular system. , 2006, Pharmacology & therapeutics.

[14]  M. Hamon,et al.  Deficiency of the 5-Hydroxytryptamine Transporter Gene Leads to Cardiac Fibrosis and Valvulopathy in Mice , 2005, Circulation.

[15]  L. Kuo,et al.  C-Reactive Protein Inhibits Endothelium-Dependent NO-Mediated Dilation in Coronary Arterioles by Activating p38 Kinase and NAD(P)H Oxidase , 2005, Arteriosclerosis, thrombosis, and vascular biology.

[16]  J. Kimura,et al.  Dual Roles of 5-Hydroxytryptamine in Ischemia-Reperfusion Injury in Isolated Rat Hearts , 2004, Journal of cardiovascular pharmacology and therapeutics.

[17]  L. Kuo,et al.  Ischemia‐reperfusion selectively impairs nitric oxide‐ mediated dilation in coronary arterioles: counteracting role of arginase , 2003, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[18]  J. Mallet,et al.  Disruption of the nonneuronal tph1 gene demonstrates the importance of peripheral serotonin in cardiac function , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Entman,et al.  Mast cells and macrophages in normal C57/BL/6 mice , 2002, Histochemistry and Cell Biology.

[20]  L. Kuo,et al.  Constitutive expression of arginase in microvascular endothelial cells counteracts nitric oxide‐mediated vasodilatory function , 2001, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[21]  D. Lamontagne,et al.  Participation of prostaglandin E2 in the endothelial protective effect of ischaemic preconditioning in isolated rat heart. , 2000, Cardiovascular research.

[22]  K. Hirata,et al.  Nitric oxide is produced via 5-HT1B and 5-HT2B receptor activation in human coronary artery endothelial cells. , 1998, The Kobe journal of medical sciences.

[23]  Á. L. López de Pablo,et al.  In Vivo Tryptophan Hydroxylase Activity in Rat Major Cerebral Arteries Is Decreased by Dorsal Raphe Nucleus Lesions , 1996, Journal of neurochemistry.

[24]  Katsuhiro Inoue,et al.  Immunocytochemical localization of aromaticl-amino acid decarboxylase and catechol-O-methyltransferase in blood vessel wall of the human dental pulp , 1996, Brain Research.

[25]  M. Curtis,et al.  Mechanism of 5‐hydroxytryptamine‐induced coronary vasodilatation assessed by direct detection of nitric oxide production in guinea‐pig isolated heart , 1996, British journal of pharmacology.

[26]  C. Tiefenbacher,et al.  Restoration of endothelium-dependent vasodilation after reperfusion injury by tetrahydrobiopterin. , 1996, Circulation.

[27]  L. Kuo,et al.  PAF attenuates endothelium-dependent coronary arteriolar vasodilation. , 1996, American Journal of Physiology.

[28]  T. Cocks,et al.  5‐Hydroxytryptamine (5‐HT) mediates potent relaxation in the sheep isolated pulmonary vein via activation of 5‐HT4 receptors , 1992, British journal of pharmacology.

[29]  M. Marcus,et al.  Understanding the Coronary Circulation Through Studies at the Microvascular Level , 1990, Circulation.

[30]  M. Sole,et al.  Serotonin Metabolism in the Normal and Failing Hamster Heart , 1979, Circulation research.

[31]  K. Inoue,et al.  Immunocytochemical localization of aromatic L-amino acid decarboxylase and catechol-O-methyltransferase in blood vessel wall of the human dental pulp. , 1996, Brain research.

[32]  D. S. Houston,et al.  Comparison of serotonergic receptor subtypes on the smooth muscle and endothelium of the canine coronary artery. , 1988, The Journal of pharmacology and experimental therapeutics.