Molecular mechanisms that control stress response and tissue remodeling by cardiometabolic and immune systems

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To elucidate pathogenic mechanisms underlying metabolic syndrome and cardiovascular diseases, we analyzed molecular control mechanisms of cellular stress response and gene transcription by cardiovascular, metabolic and immune systems. We focused on Toll-like receptor (TLR) signaling in metabolic stress response and Kruppel-like factor (KLF) family transcription factors in stress response and tissue remodeling in cardiovascular and metabolic tissues. We found that free fatty acids induce pathologies in both cardiovascular and metabolic systems. Moreover, we found that signaling mechanisms for ER stress, TLR, and reactive oxygen species play a role in the response to free fatty acids. We also showed that cardiac fibroblasts play a pivotal role in cardiac response to pressure overload by generating cardiac fibroblast-specific K1f5 knockout mice. Furthermore, we identified IGF-1 as an essential mediator produced by cardiac fibroblasts in the cardiac response to pressure overload. In metabolic systems, we found that KLF5 is also important for β cell dysfunction and the control of appetite.