Development of inhibitors for the activation of cardiovascular interstitial ceils

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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.