Aortic Valve Cyclic Stretch Causes Increased Remodeling Activity and Enhanced Serotonin Receptor Responsiveness
Aortic Valve Cyclic Stretch Causes Increased Remodeling Activity and Enhanced Serotonin Receptor Responsiveness
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DOI：
10.1016/j.athoracsur.2011.03.084
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发表时间：
2011-07-01
影响因子：
4.6
通讯作者：
Levy, Robert J.
中科院分区：
文献类型：
--
作者：
Balachandran, Kartik;Bakay, Marina A.;Levy, Robert J.
背景血清素（5-羟色胺[5 HT]）受体（5 HTR）信号传导增加与心脏瓣膜病相关。心脏瓣膜间质细胞中5 HTR信号传导的先前细胞培养研究提供了仅关于静态条件的机制见解。我们研究了主动脉瓣生物力学参与调节5 HTR表达和相关细胞外基质重塑事件的假设。采用拉伸生物反应器研究了周期性拉伸对主动脉瓣5 HT受体、表达、信号传导和细胞外基质重塑的影响，并比较了加入5 HT和（或）5 HT转运体抑制剂氟西汀的影响。在猪主动脉瓣瓣尖样本中，单独的周期性拉伸增加了增殖和胶原蛋白。然而，与静态条件不同的是，在循环牵张条件下，5-HT加氟西汀引起增殖的最大增加（p < 0.0001），并且还引起胶原蛋白（p < 0.0001）和糖胺聚糖（p < 0.0001）的显著增加。DNA微阵列数据表明，与静态相比，循环拉伸使5 HTR 2A和5 HTR 2B上调（>4.5倍）（p < 0.001），而5 HT转运蛋白的表达没有显著变化。细胞外基质基因（如I型、II型、III型胶原和蛋白多糖）也被周期性牵张上调。猪主动脉瓣瓣尖样品进行周期性拉伸上调5 HTR 2A和2B，并启动重塑活动，其特征在于增加的增殖和胶原蛋白的产生。重要的是，由于5 HTR 2A和2B表达增加而增强的5 HTR响应性导致在存在5 HT转运蛋白阻断的情况下重塑终点（增殖、胶原和GAG产生）对5 HT的显著更大的响应。(Ann Thorac Surg 2011;92：147-54）（C）2011年，胸外科医师协会
Background. Increased serotonin (5-hydroxytryptamine [5HT]) receptor (5HTR) signaling has been associated with cardiac valvulopathy. Prior cell culture studies of 5HTR signaling in heart valve interstitial cells have provided mechanistic insights concerning only static conditions. We investigated the hypothesis that aortic valve biomechanics participate in the regulation of both 5HTR expression and interrelated extracellular matrix remodeling events.Methods. The effects of cyclic stretch on aortic valve 5HTR, expression, signaling, and extracellular matrix remodeling were investigated using a tensile stretch bioreactor in studies which also compared the effects of adding 5HT and (or) the 5HT-transporter inhibitor, fluoxetine.Results. Cyclic stretch alone increased both proliferation and collagen in porcine aortic valve cusp samples. However, with cyclic stretch, unlike static conditions, 5HT plus fluoxetine caused the greatest increase in proliferation (p < 0.0001), and also caused significant in-creases in collagen (p < 0.0001) and glycosaminoglycans (p < 0.0001). The DNA microarray data demonstrated upregulation of 5HTR2A and 5HTR2B (>4.5-fold) for cyclic stretch versus static (p < 0.001), while expression of the 5HT transporter was not changed significantly. Extracellular matrix genes (eg, collagen types I, II, III, and proteoglycans) were also upregulated by cyclic stretch.Conclusions. Porcine aortic valve cusp samples subjected to cyclic stretch upregulate 5HTR2A and 2B, and also initiate remodeling activity characterized by increased proliferation and collagen production. Importantly, enhanced 5HTR responsiveness due to increased 5HTR2A and 2B expression results in a significantly greater response in remodeling endpoints (proliferation, collagen, and GAG production) to 5HT in the presence of 5HT transporter blockade. (Ann Thorac Surg 2011;92:147-54) (C) 2011 by The Society of Thoracic Surgeons