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Inhibition of 5-Hydroxytryptamine Receptor 2B Reduced Vascular Restenosis and Mitigated the β-Arrestin2-Mammalian Target of Rapamycin/p70S6K Pathway.
- Source :
-
Journal of the American Heart Association [J Am Heart Assoc] 2018 Jan 30; Vol. 7 (3). Date of Electronic Publication: 2018 Jan 30. - Publication Year :
- 2018
-
Abstract
- Background: As a monoamine neurotransmitter, 5-hydroxytryptamine (5-HT) or serotonin modulates mood, appetite, and sleep. Besides, 5-HT also has important peripheral functions. 5-HT receptor 2B (5-HT2BR) plays a key role in cardiovascular diseases, such as pulmonary arterial hypertension and cardiac valve disease. Percutaneous intervention has been used to restore blood flow in occlusive vascular disease. However, restenosis remains a significant problem. Herein, we investigated the role of 5-HT2BR in neointimal hyperplasia, a key pathological process in restenosis.<br />Methods and Results: The expression of 5-HT2BR was upregulated in wire-injured mouse femoral arteries. In addition, BW723C86, a selective 5-HT2BR agonist, promoted the injury response during restenosis. 5-HT and BW723C86 stimulated migration and proliferation of rat aortic smooth muscle cells. Conversely, LY272015, a selective antagonist, attenuated the 5-HT-induced smooth muscle cell migration and proliferation. In vitro study showed that the promigratory effects of 5-HT2BR were mediated through the activation of mammalian target of rapamycin (mTOR)/p70S6K signaling in a β-arrestin2-dependent manner. Inhibition of mammalian target of rapamycin or p70S6K mitigated 5-HT2BR-mediated smooth muscle cell migration. Mice with deficiency of 5-HT2BR showed significantly reduced neointimal formation in wire-injured arteries.<br />Conclusions: These results demonstrated that activation of 5-HT2BR and β-arrestin2-biased downstream signaling are key pathological processes in neointimal formation, and 5-HT2BR may be a potential target for the therapeutic intervention of vascular restenosis.<br /> (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)
- Subjects :
- Animals
Cell Movement drug effects
Cell Proliferation drug effects
Cells, Cultured
Disease Models, Animal
Femoral Artery drug effects
Femoral Artery enzymology
Femoral Artery injuries
Femoral Artery pathology
Male
Mice, Inbred C57BL
Mice, Knockout
Muscle, Smooth, Vascular enzymology
Muscle, Smooth, Vascular injuries
Muscle, Smooth, Vascular pathology
Myocytes, Smooth Muscle enzymology
Myocytes, Smooth Muscle pathology
Neointima
Organic Chemicals pharmacology
Rats
Receptor, Serotonin, 5-HT2B genetics
Receptor, Serotonin, 5-HT2B metabolism
Ribosomal Protein S6 Kinases, 70-kDa genetics
Signal Transduction drug effects
Vascular System Injuries enzymology
Vascular System Injuries genetics
Vascular System Injuries pathology
beta-Arrestin 2 genetics
Muscle, Smooth, Vascular drug effects
Myocytes, Smooth Muscle drug effects
Receptor, Serotonin, 5-HT2B drug effects
Ribosomal Protein S6 Kinases, 70-kDa metabolism
Serotonin 5-HT2 Receptor Antagonists pharmacology
TOR Serine-Threonine Kinases metabolism
Vascular Remodeling drug effects
Vascular System Injuries drug therapy
beta-Arrestin 2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2047-9980
- Volume :
- 7
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of the American Heart Association
- Publication Type :
- Academic Journal
- Accession number :
- 29382665
- Full Text :
- https://doi.org/10.1161/JAHA.117.006810