Excet, Inc., Fort Detrick, MD, 21702-5010, USA.
U.S. Army Center for Environmental Health Research, Fort Detrick, Maryland, MD, 21702-5010, USA.
BMC Genomics. 2019 Feb 15;20(1):141. doi: 10.1186/s12864-019-5515-6.
Heat illness remains a significant cause of morbidity in susceptible populations. Recent research elucidating the cellular mechanism of heat stress leading to heat illness may provide information to develop better therapeutic interventions, risk assessment strategies, and early biomarkers of organ damage. microRNA (miRNA) are promising candidates for therapeutic targets and biomarkers for a variety of clinical conditions since there is the potential for high specificity for individual tissues and unique cellular functions. The objective of this study was to identify differentially expressed microRNAs and their putative mRNA targets in the heart, liver, kidney, and lung in rats at three time points: during heat stress (i.e., when core temperature reached 41.8 °C), or following a 24 or 48 h recovery period.
Rats did not show histological evidence of tissue pathology until 48 h after heat stress, with 3 out of 6 rats showing cardiac inflammation and renal proteinosis at 48 h. The three rats with cardiac and renal pathology had 86, 7, 159, and 37 differentially expressed miRNA in the heart, liver, kidney, or lung, respectively compared to non-heat stressed control animals. During heat stress one differentially expressed miRNA was found in the liver and five in the lung, with no other modulated miRNA after 24 h or 48 h in animals with no evidence of organ injury. Pathway enrichment analysis revealed enrichment in functional pathways associated with heat stress, with the greatest effects observed in animals with histological evidence of cardiac and renal damage at 48 h. Inhibiting miR-21 in cultured cardiomyocytes increased the percent apoptotic cells five hours after heat stress from 70.9 ± 0.8 to 84.8 ± 2.2%.
Global microRNA and transcriptomics analysis suggested that perturbed miRNA due to heat stress are involved in biological pathways related to organ injury, energy metabolism, the unfolded protein response, and cellular signaling. These miRNA may serve as biomarkers of organ injury and potential pharmacological targets for preventing heat illness or organ injury.
热应激疾病仍然是易感人群发病率的一个重要原因。最近的研究阐明了导致热应激疾病的细胞热应激机制，这可能为开发更好的治疗干预措施、风险评估策略以及器官损伤的早期生物标志物提供信息。microRNA（miRNA）是治疗靶点和多种临床情况生物标志物的有前途的候选物，因为它们有可能针对个别组织和独特的细胞功能具有高度特异性。本研究的目的是在三个时间点（即核心体温达到 41.8°C 时、热应激后 24 小时或 48 小时恢复期间）在大鼠的心脏、肝脏、肾脏和肺中鉴定差异表达的 microRNAs 及其推定的 mRNA 靶标。
直到热应激后 48 小时，大鼠才出现组织病理学证据，6 只大鼠中有 3 只在 48 小时时出现心脏炎症和肾脏蛋白症。3 只具有心脏和肾脏病理学的大鼠的心脏、肝脏、肾脏或肺中分别有 86、7、159 和 37 个差异表达 miRNA，与非热应激对照动物相比。在热应激期间，肝脏中发现了一个差异表达 miRNA，肺中有五个，在没有器官损伤证据的动物中，24 小时或 48 小时后没有其他调节的 miRNA。途径富集分析显示，与热应激相关的功能途径富集，在 48 小时时有组织学证据的心脏和肾脏损伤的动物中观察到最大的影响。在培养的心肌细胞中抑制 miR-21 可使热应激后五小时的凋亡细胞百分比从 70.9±0.8 增加到 84.8±2.2%。
全球 microRNA 和转录组学分析表明，热应激引起的失调 miRNA 参与与器官损伤、能量代谢、未折叠蛋白反应和细胞信号转导相关的生物学途径。这些 miRNA 可能作为器官损伤的生物标志物和预防热应激疾病或器官损伤的潜在药物靶点。
