Whole genome transcriptomic reveals heat stroke molecular signatures in humans
Whole genome transcriptomic reveals heat stroke molecular signatures in humans
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DOI：
10.1113/jp284031
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发表时间：
2023-04-05
影响因子：
5.5
通讯作者：
Yezli, Saber
中科院分区：
文献类型：
--
作者：
Bouchama, Abderrezak;Rashid, Mamoon;Yezli, Saber
进化热休克反应（HSR）保护大多数生物物种，包括人类，免受热诱导的大分子损伤。然而，其在中暑发病机制中的作用尚不清楚。我们检测了暴露于相同高温环境条件下的一组受试者外周血单核细胞的全基因组转录组，其中19人发生中暑，19人未发生中暑。中暑患者入院时的平均直肠温度为41.7 ± 0.8 ℃，8例处于深度昏迷（格拉斯哥昏迷评分= 3）。转录组显示，在超过一半的整个伴侣基因组中涉及的基因相对于热应激对照差异表达。这些包括热休克蛋白，辅伴侣蛋白，伴侣蛋白基因，表明一个强大的HSR。差异表达基因还编码与未折叠蛋白反应、DNA修复、能量代谢、氧化应激和免疫相关的蛋白质。该分析预测了蛋白质组网络和能量生产的扰动。冷却疗法减弱了这些变化，但没有完全恢复体内平衡。我们通过实时聚合酶链反应验证了显著表达的基因。这些发现揭示了中暑的分子特征。他们还建议，一个强大的HSR可能不足以防止热损伤。压倒性的蛋白质毒性和能量衰竭可能发挥致病作用。
An evolutionary heat shock response (HSR) protects most living species, including humans, from heat-induced macromolecular damage. However, its role in the pathogenesis of heat stroke is unknown. We examined thewhole genome transcriptome in peripheral blood mononuclear cells of a cohort of subjects exposed to the same high environmental heat conditions, who developed heat stroke (n = 19) versus those who did not (n = 19). Patients with heat stroke had a mean rectal temperature at admission of 41.7 +/- 0.8 degrees C, and eight were in deep coma (Glasgow Coma Score = 3). The transcriptome showed that genes involved in more than half of the entire chaperome were differentially expressed relative to heat stress control. These include the heat shock protein, cochaperone, and chaperonin genes, indicating a robust HSR. Differentially expressed genes also encoded proteins related to unfolded protein response, DNA repair, energy metabolism, oxidative stress, and immunity. The analysis predicted perturbations of the proteome network and energy production. Cooling therapy attenuated these alterations without complete restoration of homeostasis. We validated the significantly expressed genes by a real-time polymerase chain reaction. The findings reveal the molecular signature of heat stroke. They also suggested that a powerful HSR may not be sufficient to protect against heat injury. The overwhelming proteotoxicity and energy failure could play a pathogenic role.