transforming-growth-factor-beta and sarpogrelate

To evaluate the effects of the 5-HT2 receptor antagonist sarpogrelate hydrochloride (sarpogrelate) on platelet responses in arteriosclerosis obliterans (ASO), we examined platelet aggregation and its relationships to platelet-derived growth factor (PDGF), soluble P-selectin (sP-selectin), and transforming growth factor-beta 1 (TGF-beta1). Circulating plasma levels of PDGF and sP-selectin in 13 patients with ASO after 1 week of medication with sarpogrelate were significantly lower than those before medication. In contrast, circulating plasma levels of TGF-beta1 after medication were significantly higher than those before medication. When platelet-rich plasma obtained from ASO patients after medication was stimulated with adenosine diphosphate (ADP) or collagen, platelet aggregation was suppressed compared with rates before medication. Significant decreases in levels of PDGF, sP-selectin and TGF-beta1 released from platelets in response to 5 micromol/l ADP and 1 microg/ml collagen after taking of sarpogrelate were found. There were close correlations between platelet aggregation and respective molecules released from platelets. In conclusion, since platelet activation is involved in pathogenesis of thrombotic disease, sarpogrelate may suppress the development of obstructive arteriosclerosis. PDGF and TGF-beta1, as well as sP-selectin, appear to be useful markers for clinical evaluation of anti-platelet drugs.

Topics: Adenosine Diphosphate; Aged; Arteriosclerosis Obliterans; Case-Control Studies; Collagen; Female; Humans; Linear Models; Male; Middle Aged; P-Selectin; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Platelet-Derived Growth Factor; Serotonin Antagonists; Succinates; Transforming Growth Factor beta; Transforming Growth Factor beta1

5-hydroxytryptamine (5-HT) receptors are upregulated in activated hepatic stellate cells (HSCs), and are therefore thought to play an important role in their activation.. The aim of this study was to determine whether 5-HT2A receptor antagonists affect the activation or apoptosis of HSCs in vitro and/or in vivo.. For the in vitro experiments, the viability, apoptosis and wound healing ability of LX-2 cells were examined after treatment with various 5-HT2A receptor antagonists. Levels of HSC activation markers (procollagen type I, α-SMA, TGF-β and Smad 2/3) were measured. For in vivo experiments, rats were divided into three groups: (i) a control group, (ii) a disease group, in which cirrhosis was induced by thioacetamide (iii) a treatment group, in which cirrhosis was induced and a 5-HT2A receptor antagonist (sarpogrelate, 30 mg/kg) was administered.. 5-HT2A , but not 5-HT2B receptor mRNA increased with time upon HSC activation. 5-HT2A receptor antagonists (ketanserin and sarpogrelate) inhibited viability and wound healing in LX-2 cells and induced apoptosis. Expression of α-SMA and procollagen type I was also inhibited. In the in vivo study, lobular inflammation was reduced in the sarpogrelate-treated group, but there was only slight and statistically insignificant attenuation of periportal fibrosis. Expression of α-SMA, TGF-β and Smad 2/3 was also reduced in the treatment group.. 5-HT2A receptor antagonists can reduce inflammation and the activation of HSCs in this cirrhotic model.

Topics: Actins; Animals; Apoptosis; Cell Line; Cell Survival; Collagen Type I; Dose-Response Relationship, Drug; Hepatic Stellate Cells; Humans; Ketanserin; Liver Cirrhosis, Experimental; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptor, Serotonin, 5-HT2A; Ritanserin; RNA, Messenger; Serotonin 5-HT2 Receptor Antagonists; Smad2 Protein; Smad3 Protein; Succinates; Thioacetamide; Time Factors; Transforming Growth Factor beta; Wound Healing

Chronic graft-versus-host disease (cGVHD) is a frequent complication of allogenic bone marrow transplantation. Even with aggressive treatment, cGVHD is associated with a significant degree of morbidity and mortality. cGVHD resembles autoimmune disorder, particularly systemic sclerosis (SSc). Sarpogrelate hydrochloride (SH) is an antagonist of the 5-hydroxytryptamine2A (5HT2A) receptor and has been reported to be effective in the treatment of systemic sclerosis (SSc) patients with Raynaud phenomenon. We used SH to treat a cGVHD patient, and we measured plasma PDGF and total TGF-beta levels. After SH treatment, his plasma PDGF and total TGF-beta levels decreased, and he noticed improvement in his skin pigmentation. In the present case, SH may have improved the skin lesion by inhibiting the synthesis of PDGF and TGF-beta.

Topics: Adult; Bone Marrow Transplantation; Chronic Disease; Graft vs Host Disease; Humans; Male; Receptors, Platelet-Derived Growth Factor; Serotonin Antagonists; Succinates; Transforming Growth Factor beta

The plasma concentration of 5-hydroxytryptamine (5-HT) in diabetic patients is higher than that in normal subjects. Since recent reports have demonstrated the presence of 5-HT2A receptor in glomerular mesangial cells, it is possible that 5-HT may be involved in the development of diabetic nephropathy through the 5-HT2A receptor in mesangial cells. Because expansion of the glomerular mesangial lesion is a characteristic feature of diabetic nephropathy, we examined the effect of 5-HT on the production of type IV collagen by human mesangial cells.. Human mesangial cells were incubated with 5-HT with or without 5-HT receptor antagonists, protein kinase C (PKC) inhibitor or transforming growth factor-beta (TGF-beta) antibody. Type IV collagen mRNA and protein concentration in medium were measured by Northern blot analysis and enzyme-linked immunosorbent assay (ELISA), respectively. TGF-beta mRNA and bioactivity in the medium were measured by Northern blot analysis and bioassay using mink lung epithelial cells, respectively.. 5-HT stimulated the production of type IV collagen by human mesangial cells, which was inhibited by ketanserin and sarpogrelate hydrochloride, 5-HT2A receptor antagonists, but not by ondansetron, a 5-HT3 receptor antagonist. 5-HT increased the bioactivities of both active and total TGF-beta. However, the 5-HT-enhanced production of type IV collagen was completely inhibited by an anti-TGF-beta antibody. Furthermore, a PKC inhibitor, calphostin C, inhibited the 5-HT-induced increase in type IV collagen secretion, and the activity of membrane PKC was increased by 5-HT. Phorbol ester activated type IV collagen production as well as active and total TGF-beta. Calphostin C completely inhibited the 5-HT-enhanced activity of active TGF-beta, but did not inhibit exogenous TGF-beta-induced increase in type IV collagen secretion.. Our results suggest that 5-HT-enhanced production of type IV collagen by human mesangial cells is mediated by activation of PKC and subsequent increase in active TGF-beta activity.

Topics: Cells, Cultured; Collagen; Diabetic Nephropathies; Glomerular Mesangium; Humans; Ketanserin; Kinetics; Protein Kinase C; Receptor, Serotonin, 5-HT2A; Receptors, Serotonin; RNA, Messenger; Serotonin; Serotonin Antagonists; Succinates; Transforming Growth Factor beta