Molecular mechanism of organ remodeling : Gene transcription and cell-cell interaction in mesenchymal

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External stress activates local cells of the mesenchymal origin (e.g., fibroblasts and smooth muscle cells) and inflammatory cells. Interactions between these cells promote fibrosis, organ hypertrophy, and structural remodeling. These changes affect the function of organs and result in organ failure including heart failure, renal failure, and liver failure. Thus, elucidation of molecular mechanisms underlying the tissue remodeling would lead to development novel therapeutic strategies for protection of normal organ function. We identified a Kruppel-like zinc finger transcription factor BTEB2 that is important for atherosclerosis, restenosis after angioplasty, tissue fibrosis, and cardiac hypertrophy. We also found that the ageing related factor Klotho inhibits tissue remodeling of the cardiovascular system. In this research project, we have analyzed transcriptional regulation and signal transduction that control tissue remodeling. The goals of the project were : 1)elucidation of the transcription factor network involved in activation of mesenchymal cells in tissue remodeling ; 2)elucidation of signal transduction mechanisms involved in the protective function of the Klotho factor against stress in the cardiovascular system ; and 3)development of drugs targeting transcription factors and humoral factors that are important for remodeling. We demonstrated that KLF5 plays essential roles in stress responses in both cardiovascular and metabolic systems. KLF5 interacts with transcription factors, such as PPARγ and RARα, cofactors, such as p300, and apoptosis-related genes, such as PARP to control stress response and to mediate tissue remodeling. To develop novel therapeutics targeting the KLF5 molecular network, we found a synthetic retinoid Am80 disrupts the interaction between KLF5 and RARα and inhibits KLF5's function. We showed that Am80 inhibited neointima formation and atherogenesis. We also demonstrate that klotho exhibits vascular protective effects.