| 研究実績の概要 |
Diabetes accelerates vascular ageing when excess ROS exceed antioxidant capacity, leading to SASP, vascular dysfunction and vessel rarefaction. Therefore, we tested whether Nox2 contributes to coronary dysfunction in diet induced early-stage diabetes (B6D2 hybrid mice) induced by chronic high fat diet (HFD) and increased salt intake (1% NaCl water) in mice treated with and without apocynin (Nox2 inhibitor). Synchrotron microangiography revealed that the coronary capacity to produce NO was diminished with insulin resistance onset, and was exacerbated by apocynin treatment, suggesting that Nox2 overactivation in insulin resistance reduces NO bioavailability. In SAMP8 mice glycolysis was inhibited and abnormal purine metabolism increased xanthine oxidase activation and ROS generation on HFD, leading to SASP activation and microvascular dysfunction. In the absence of insulin resistance, Nox2 activation was essential for NO mediated vasodilation and limiting senescence progression. To investigate SASP activation we used CRISPR/Cas9 to generate Nfkbib gene deletion mice that are unable to activate NFkB signaling. We characterised the diet induced insulin resistance model with transcriptome (RNAseq) and proteome profiling. B6D2 mice were found to develop mild coronary dysfunction due to elevated ROS production, metabolic inflexibility and mitochondrial dysfunction. We found that insulin resistance greatly increases endothelin production and ROS through Nox2 to reduce NO bioavailability. iNOS upregulation was enhanced and promoted p53 activation in senescent mice.
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