n-(1-methyl-5-indolyl)-n--(3-methyl-5-isothiazolyl)urea and dironyl

Cardiac allograft vasculopathy (CAV) is the main obstacle for long-term survival after heart transplantation. Alloimmune mediated chronic vascular rejection results in several mechanisms like platelet activation, immigration of inflammatory cells through the endothelial layer and proliferation and migration of smooth muscle cells (SMCs). Serotonin (5-HT) promotes these processes via activation of 5-HT. CBA/JRj mice recieved aortic grafts from C57BL/6 mice. After transplantation until recovery of organs, recipients were treated with serotonin receptor antagonists: sarpogrelate (5-HT. Elevated serum serotonin levels were significantly reduced after 5-HT. Inhibition of the 5HT/5-HT

Topics: Animals; Aorta; Cell Proliferation; Female; Graft Rejection; Heart Transplantation; Humans; Indoles; Lisuride; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Models, Animal; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Succinates; Transendothelial and Transepithelial Migration; Transplantation, Homologous; Urea

Release of 5-hydroxytryptamine (5-HT; serotonin) from activated platelets following microvascular injury leads to tissue fibrosis. 5-HT strongly induces extracellular matrix synthesis in dermal fibroblasts in a transforming growth factor beta 1 (TGF-β1)-dependent manner.. To evaluate anti-fibrotic properties of inhibitors of 5-HT. Stimulation of HADF cells with 5-HT/TGF-β1 led to the increased expression of pro-fibrotic genes which was significantly reduced by both terguride and SB204741. Expression of anti-fibrotic genes was not affected upon incubation with the inhibitors. In 5-HT-stimulated HADF, treatment with terguride and SB204741 decreased type I collagen and α-SMA. In 5-HT/TGF-β1 stimulated HADF, terguride and SB204741 treatment reduced ERK1/2 and STAT3 phosphorylation but did not influence Smad3 phosphorylation.. Terguride and SB204741 reduce pro-fibrotic potential of HADF cells and suppress TGF-β1-mediated non-canonical pathways, ERK1/2 and STAT3 which have been implicated in the regulation of pro-fibrotic genes and in the development of fibrosis. Taken together, our data suggest that 5-HT inhibitors might reduce fibrosis via suppression of TGF-beta1-mediated non-canonical signaling pathways. These observations have important therapeutic implications for fibrotic disorders like scleroderma.

Topics: Adult; Cells, Cultured; Extracellular Matrix Proteins; Extracellular Signal-Regulated MAP Kinases; Female; Fibroblasts; Fibrosis; Gene Expression Regulation; Humans; Indoles; Lisuride; Phenotype; Phosphorylation; Receptor, Serotonin, 5-HT2B; Scleroderma, Systemic; Serotonin; Serotonin 5-HT2 Receptor Antagonists; Signal Transduction; Skin; STAT3 Transcription Factor; Transforming Growth Factor beta1; Urea