Development of inhibitors for the activation of cardiovascular interstitial ceils

心血管系统间质细胞的激活在心脏和血管疾病的发生和发展中起着关键作用，包括心脏肥厚、心力衰竭和动脉粥样硬化。间质细胞如成纤维细胞和平滑肌细胞通过产生生长因子、细胞外基质和基质金属蛋白酶来促进结构重塑。因此，抑制这些细胞类型激活的药物有可能成为心血管疾病的新疗法。然而，关于细胞活化的转录控制机制知之甚少。本研究的目标是：1)通过改变转录因子的连接来确定抑制平滑肌细胞激活的化合物；2)确定参与心脏间质细胞激活的转录因子；3)使转基因大鼠分泌衰老相关蛋白Klotho，该蛋白被认为在衰老过程中对心血管系统起保护作用。我们发现了几种可以抑制平滑肌细胞激活的化合物，并在培养的平滑肌细胞和体内检测了它们的活性。我们分析了血管紧张素n激活心脏间质细胞的基因表达模式，发现了包括BTEB2在内的几个转录因子可以被血管紧张素II诱导。我们构建了由乳白蛋白启动子驱动的Klotho转基因构建体，并获得了转基因大鼠系。

Activation of interstitial cells of the cardiovascular system plays pivotal roles in initiation and progression of cardiac and vascular diseases including cardiac hypertrophy, heart failure, and atherosclerosis. Responding to external stresses, interstitial cells such as fibroblasts and smooth muscle cells promote structural remodeling by producing growth factors, extracellular matrices, and matrix metalloproteases. Thus, drugs that inhibit activation of these cell-types would have potential for novel treatment of cardiovascular diseases. However, little has been known regarding transcriptional control mechanisms of the activation of the cells. The goals of the present studies were : 1) to identify compounds that inhibited activation of smooth muscle cells by modifying the Junction of transcription factors, 2) to identify transcription factors involved in activation of cardiac interstitial cells, and 3) to generate transgenic rats secreting ageing-related protein Klotho, which is though to play a protective role for the cardiovascular system in ageing, into milk. We identified several compounds that could inhibit activation of smooth muscle cells and examined their activities in cultured smooth muscle cells and in vivo. We analyzed expression patterns of genes in activation of cardiac interstitial cells by angiotensin n and found several transcription factors including BTEB2 that induced by angiotensin II. We generated a Klotho transgene construct driven by the lactoalbumin promoter and obtained transgenic rat lines.