游離輻射誘發血管平滑肌細胞粒線體斷裂及表現型改變

Ionizing radiation (IR) is a mainstay of modern cancer treatment. Because life expectancy of cancer survivors is extending, it is important to better understand late complications from definitive radiotherapy such as atherosclerosis. Upon exposure to cardiovascular risk factors, vascular smooth muscle cells (VSMC) in arterial wall switch on a nuclear factor kappa B (NF-B)-dependent gene expression program for cytokines and matrix proteins production, and assume a synthetic phenotype to facilitate atherogenesis. However, whether biased mitochondrial dynamics cross-talk with NF-B pathway for phenotypic switch remains unknown.
In this study, we first test if IR induces phenotypic switch in VSMC. Indeed, IR exposure leads to nuclear localization of p65, biased mitochondrial dynamics towards fission, cellular senescence, apoptosis, and a switch to synthetic phenotype among the residual surviving VSMC. However, inhibition of mitochondrial fission with mitochondrial division inhibitor (Mdivi1) does not interfere with IR-induced p65 nuclear localization or phenotypic switch. Neither does inhibiting p65 nuclear import with JSH23 block IR-induced mitochondrial fission. Cyclosporine A (CsA) efficiently prevents IR-induced p65 nuclear import, but it synergizes with IR to promote mitochondrial fission. Interestingly, CsA treatment does not reverse IR-induced phenotypic switch.
Our observations suggest that IR activates two parallel intracellular signaling pathways, namely NF-B-dependent synthetic gene programs and mitochondrial fission. CsA differentially targets these two pathways. These findings provide new mechanistic link for IR-related vasculopathy and warrant further studies for improving cancer survivorship.