Marinobufagenin stimulates fibroblast collagen production and causes fibrosis in experimental uremic cardiomyopathy
Marinobufagenin stimulates fibroblast collagen production and causes fibrosis in experimental uremic cardiomyopathy
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DOI：
10.1161/01.hyp.0000252409.36927.05
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发表时间：
2007-01-01
期刊：
影响因子：
8.3
通讯作者：
Shapiro, Joseph I.
中科院分区：
文献类型：
--
作者：
Elkareh, Jihad;Kennedy, David J.;Shapiro, Joseph I.
我们最近观察到，大鼠的实验性肾衰竭伴随着强心类固醇、海蟾蜍配基（MBG）循环浓度的增加和严重的心脏纤维化。我们进行了以下研究来检验 MBG 是否可以直接刺激心脏成纤维细胞胶原蛋白的产生。使用实验性肾衰竭（PNx）的5/6肾切除模型、MBG输注（MBG）、MBG免疫后的PNx以及伴随的PNx和肾上腺切除术进行体内研究。使用 Millar 导管和免疫组织化学进行生理测量。然后用培养的分离的心脏成纤维细胞进行体外研究。我们观察到 PNx 和 MBG 会增加 MBG 水平、血压、心脏大小、舒张功能受损，并导致心脏纤维化。接受 MBG 免疫以及同时进行 PNx 和肾上腺切除术后，PNx 的血压与 PNx 相似，但心脏肥大、舒张功能障碍和心脏纤维化较少。 MBG 在 1 nM 浓度下诱导培养的心脏成纤维细胞中前胶原-1 表达增加。前胶原蛋白表达的增加伴随着胶原蛋白翻译的增加和前胶原蛋白 1 mRNA 的增加，但前胶原蛋白 1 的稳定性没有任何明显的增加。通过施用酪氨酸磷酸化、Src 激活、表皮生长因子受体反式激活和 N-乙酰半胱氨酸抑制剂，可以防止 MBG 对成纤维细胞的刺激。基于这些发现，我们提出MBG直接诱导成纤维细胞胶原蛋白表达增加，并且我们认为这对于实验性肾衰竭所见的心脏纤维化可能很重要。
We have observed recently that experimental renal failure in the rat is accompanied by increases in circulating concentrations of the cardiotonic steroid, marinobufagenin (MBG), and substantial cardiac fibrosis. We performed the following studies to examine whether MBG might directly stimulate cardiac fibroblast collagen production. In vivo studies were performed using the 5/6th nephrectomy model of experimental renal failure (PNx), MBG infusion ( MBG), PNx after immunization against MBG, and concomitant PNx and adrenalectomy. Physiological measurements with a Millar catheter and immunohistochemistry were performed. In vitro studies were then pursued with cultured isolated cardiac fibroblasts. We observed that PNx and MBG increased MBG levels, blood pressure, heart size, impaired diastolic function, and caused cardiac fibrosis. PNx after immunization against MBG and concomitant PNx and adrenalectomy had similar blood pressure as PNx but less cardiac hypertrophy, diastolic dysfunction, and cardiac fibrosis. MBG induced increases in procollagen-1 expression by cultured cardiac fibroblasts at 1 nM concentration. These increases in procollagen expression were accompanied by increases in collagen translation and increases in procollagen-1 mRNA without any demonstrable increase in procollagen-1 protein stability. The stimulation of fibroblasts with MBG could be prevented by administration of inhibitors of tyrosine phosphorylation, Src activation, epidermal growth factor receptor transactivation, and N-acetyl cysteine. Based on these findings, we propose that MBG directly induces increases in collagen expression by fibroblasts, and we suggest that this may be important in the cardiac fibrosis seen with experimental renal failure.