A dose-dependent perturbation in cardiac energy metabolism is linked to radiation-induced ischemic heart disease in Mayak nuclear workers

Epidemiological studies show a significant increase in ischemic heart disease (IHD) incidence associated with total external gamma-ray dose among Mayak plutonium enrichment plant workers. Our previous studies using mouse models suggest that persistent alteration of heart metabolism due to the inhibition of peroxisome proliferator-activated receptor (PPAR) alpha accompanies cardiac damage after high doses of ionising radiation. The aim of the present study was to elucidate the mechanism of radiation-induced IHD in humans. The cardiac proteome response to irradiation was analysed in Mayak workers who were exposed only to external doses of gamma rays. All participants were diagnosed during their lifetime with IHD that also was the cause of death. Label-free quantitative proteomics analysis was performed on tissue samples from the cardiac left ventricles of individuals stratified into four radiation dose groups (0 Gy, < 100 mGy, 100–500 mGy, and > 500 mGy).
The groups could be separated using principal component analysis based on all proteomics features. Proteome profiling showed a dose-dependent increase in the number of downregulated mitochondrial and structural proteins. Both proteomics and immunoblotting showed decreased expression of several oxidative stress responsive proteins in the irradiated hearts. The phosphorylation of transcription factor PPAR alpha was increased in a dose-dependent manner, which is indicative of a reduction in transcriptional activity with increased radiation dose. These data suggest that chronic external radiation enhances the risk for IHD by inhibiting PPAR alpha and altering the expression of mitochondrial, structural, and antioxidant components of the heart.

流行病学研究表明，马亚克（Mayak）钚浓缩厂工人的缺血性心脏病（IHD）发病率与外照射总γ射线剂量呈显著正相关。我们此前基于小鼠模型的研究提示，高剂量电离辐射暴露后，心脏损伤会伴随过氧化物酶体增殖物激活受体α（PPARα）受抑制所引发的心脏代谢持续紊乱。本研究旨在阐明辐射诱导人类罹患IHD的分子机制。本研究对仅接受外照射γ射线的马亚克工人的心脏蛋白质组辐射应答情况进行了分析。所有受试者生前均被诊断为IHD，且该疾病亦是其致死原因。我们对受试者左心室组织样本开展无标记定量蛋白质组学分析，将样本按辐射剂量分为四组：0 Gy、<100 mGy、100–500 mGy及>500 mGy。
基于所有蛋白质组学特征，可通过主成分分析对四组样本进行有效区分。蛋白质组谱分析显示，线粒体蛋白与结构蛋白的下调数量随辐射剂量升高呈剂量依赖性增加。蛋白质组学与免疫印迹实验均证实，受辐射心脏内多种氧化应激应答蛋白的表达水平显著下调。转录因子PPARα的磷酸化水平随辐射剂量升高呈剂量依赖性上升，这提示其转录活性随辐射剂量增加而降低。上述数据表明，慢性外照射可通过抑制PPARα、改变心脏线粒体、结构蛋白及抗氧化组分的表达水平，提升个体罹患IHD的风险。