Serotonin mechanisms in heart valve disease I -: Serotonin-induced up-regulation of transforming growth factor-β1 via G-protein signal transduction in aortic valve interstitial cells
Serotonin mechanisms in heart valve disease I -: Serotonin-induced up-regulation of transforming growth factor-β1 via G-protein signal transduction in aortic valve interstitial cells
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DOI：
10.1016/s0002-9440(10)64489-6
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发表时间：
2002-12-01
影响因子：
6
通讯作者：
Levy, RJ
中科院分区：
文献类型：
--
作者：
Jian, B;Xu, J;Levy, RJ
与5-羟色胺[5-羟色胺(5-HT)]水平升高相关的临床疾病，如类癌综合征，以及5-羟色胺激动剂(如芬氟胺)的使用，都与瓣膜病有关，特征是瓣膜和心内膜增生性病变，细胞外基质增加。此外，已证实5-羟色胺通过G蛋白信号转导上调系膜细胞转化生长因子-β的表达。我们研究了心脏瓣膜间质细胞对5-羟色胺的暴露增加可能导致转化生长因子-β1的表达和活性增加的假说，这是因为5-羟色胺受体介导的信号转导伴随Galphaq的激活，从而导致磷脂酶C的上调。因此，在本研究中，我们利用免疫组织化学技术对取回的类癌和正常瓣膜尖进行了临床病理研究，以检测转化生长因子-β1和其他与转化生长因子-β1表达相关的蛋白的存在，包括转化生长因子-β受体I和II、潜在的转化生长因子-β相关肽(LAP)和α-平滑肌肌动蛋白。类癌瓣膜尖端可见广泛分布的平滑肌肌动蛋白，累及类癌结节周围的间质细胞；这些细胞也呈Lay阳性。正常瓣膜尖端仅局灶性表达平滑肌肌动蛋白和LAP。在绵羊主动脉瓣间质细胞培养中，5-羟色胺可诱导转化生长因子-β1基因的表达，并增加转化生长因子-β1的活性。在所研究的剂量下，5-羟色胺也增加了胶原的生物合成。此外，向SAVEC培养物中添加转化生长因子-β1可以增加硫酸多糖和透明质酸的产量。此外，通过构建具有活性的Galphaq突变体腺病毒表达载体(Q209L-Galphaq)过表达Galphaq，可增加磷脂酶C的活性，上调转化生长因子-β的表达和活性。这些结果有力地支持了G蛋白相关的信号转导参与了5-羟色胺上调转化生长因子-β1的观点。总之，5-羟色胺相关的瓣膜疾病可能部分是由于转化生长因子-β1的作用机制。
Clinical disorders associated with increased serotonin [5-hydroxytryptamine (5-HT)] levels, such as carcinoid syndrome, and the use of serotonin agonists, such as fenfluoramine have been associated with a valvulopathy characterized by hyperplastic valvular and endocardial lesions with increased extracellular matrix. Furthermore, 5-HT has been demonstrated to up-regulate transforming growth factor (TGF)-beta in mesangial cells via G-protein signal transduction. We investigated the hypothesis that increased exposure of heart valve interstitial cells to 5-HT may result in increased TGF-beta1 expression and activity because of serotonin receptor-mediated signal transduction with activation of Galphaq, and subsequently up-regulation of phospholipase C. Thus, in the present study we performed a clinical-pathological investigation of retrieved carcinoid and normal valve cusps using immunohistochemical techniques to detect the presence of TGF-beta1 and other proteins associated with TGF-beta expression, including TGF-beta receptors I and II, latent TGF-beta-associated peptide (LAP), and alpha-smooth muscle actin. Carcinoid valve cusps demonstrated the unusual finding of widespread smooth muscle actin involving the interstitial cells in the periphery of carcinoid nodules; these same cells were also positive for LAY. Normal valve cusps were only focally positive for smooth muscle actin and LAP. In sheep aortic valve interstitial cell cultures 5-HT induced TGF-beta1 mRNA production and increased TGF-beta1 activity. 5-HT also increased collagen biosynthesis at the dosages studied. Furthermore, TGF-beta1 added to SAVIC cultures increased the production of sulfated glycan and hyaluronic acid. in addition, overexpression of Galphaq using an adenoviral expression vector for a constitutively active Galphaq mutant (Q209L-Galphaq) resulted in increased phospholipase C activity as well as up-regulation of TGF-beta expression and activity. These results strongly support the view that G-protein-related signal transduction is involved in 5-HT up-regulation of TGF-beta1. In conclusion, 5-HT-associated valve disease may be, in part, because of TGF-beta1 mechanisms.