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Alterations in Tissue microRNA after Heat Stress in the Conscious Rat: Potential Biomarkers of Organ-Specific Injury

ABSTRACT: Heat illness, which remains an occupational and environmental hazard, can be caused by excessive strain or heat load in combination with other factors. In the 10-year period from 1999 to 2009, an average of 658 annual heat-related deaths occurred in the United States. While heat stress at the cellular level has been studied, a paucity of risk assessment and injury biomarkers as well as therapeutic interventions remains. To identify novel biomarkers and to further understand the molecular mechanisms of heat stress, we identified differentially expressed microRNAs (miRNAs) in the heart, liver, and kidney from a conscious rat model at three time points. We distinguished the effect in animals with histopathological evidence of heart injury from those without evidence of organ injury. In animals without evidence of injury, we identified a total of 45 unique modulated miRNAs, whereas in the three animals with evidence of injury, we identified 171 unique differentially expressed miRNAs. The majority of the perturbed miRNAs were both time and tissue specific. Using the data from a microarray companion study, we identified the mRNAs that are the predicted targets of the differentially expressed miRNAs and performed pathway enrichment analysis. The enrichment analysis suggested that the perturbed miRNAs are involved in biological pathways related to energy metabolism, the unfolded protein response, and organ injury. These miRNAs may serve as organ-specific heat stress biomarkers of exposure or effect, as well as identify potential targets of heat illness prevention.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE81331 | GEO | 2016/08/10

SECONDARY ACCESSION(S): PRJNA321305

REPOSITORIES: GEO

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Project description:Background: The in vivo gene response associated with hyperthermia and subsequent return to homeostasis or development of heat illness is poorly understood. Early activation of gene networks in the heat stress response is likely to lead to the systemic inflammation, multi-organ functional impairment, and other pathophysiological states characteristic of heat illness. Here, we perform an unbiased global characterization of the multi-organ gene response using an in vivo model of heat stress in the conscious rat. Results: Rats were subjected to elevated temperatures until implanted thermal probes indicated a maximal core temperature of 41.8 °C (Tc,Max). Liver, lung, kidney, and heart were harvested at Tc,Max, 24 hours, and 48 hours after heat stress in groups of experimental animals and time-matched controls kept at ambient temperature. Clinical chemistries suggested abnormal function in liver, kidney, and lung at Tc,Max, and cardiac histopathology at 48 hours supported persistent cardiac damage in 3 out of 6 animals. Microarray analysis identified 78 differentially expressed genes common to all 4 organs at Tc,Max (i.e., the consensus heat stress response). Gene set enrichment analysis of gene ontology terms identified 25 biological processes in 4 general gene ontology categories: protein folding, regulation of apoptosis, response to cytokines, and transcriptional responses. Functional analysis clustering of the 78 differentially expressed genes in the consensus heat stress response also identified functional categories of protein folding and regulation of apoptosis. Self-organizing maps identified gene-specific signatures corresponding to protein folding disorders specific to only heat-stressed rats with histopathologic evidence of cardiac injury at 48 hours. Enrichment analysis of differentially expressed proteins in heat-injured hearts at 48 hours corroborated gene enrichment analysis results. Quantitative proteomics analysis by iTRAQ demonstrated that differential protein expression was not comparable to transcript expression at Tc,Max and 24 hours. However, the profile of differentially expressed proteins closely matched the transcriptomic profile in heat-injured animals at 48 hours. Pathway analysis at both the transcript and protein levels supported catastrophic deficits in energetics and cellular metabolism, chronic proteotoxic response, and activation of the unfolded protein response. Calculation of protein super-saturation scores demonstrated an increased propensity of proteins to aggregate in the hearts of heat-injured animals at 48 hours, consistent with accumulation of misfolded proteins. Conclusions: Global transcriptomic and proteomic analysis identified networks of genes and proteins initiating an unfolded protein response, metabolic dysfunction, and mitochondrial energy crisis in animals with histopathologic evidence of persistent heat injury, providing the basis for a systems-level physiological model of heat illness and recovery.

Project description:Background: The in vivo gene response associated with hyperthermia and subsequent return to homeostasis or development of heat illness is poorly understood. Early activation of gene networks in the heat stress response is likely to lead to the systemic inflammation, multi-organ functional impairment, and other pathophysiological states characteristic of heat illness. Here, we perform an unbiased global characterization of the multi-organ gene response using an in vivo model of heat stress in the conscious rat. Results: Rats were subjected to elevated temperatures until implanted thermal probes indicated a maximal core temperature of 41.8 M-BM-0C (Tc,Max). Liver, lung, kidney, and heart were harvested at Tc,Max, 24 hours, and 48 hours after heat stress in groups of experimental animals and time-matched controls kept at ambient temperature. Clinical chemistries suggested abnormal function in liver, kidney, and lung at Tc,Max, and cardiac histopathology at 48 hours supported persistent cardiac damage in 3 out of 6 animals. Microarray analysis identified 78 differentially expressed genes common to all 4 organs at Tc,Max (i.e., the consensus heat stress response). Gene set enrichment analysis of gene ontology terms identified 25 biological processes in 4 general gene ontology categories: protein folding, regulation of apoptosis, response to cytokines, and transcriptional responses. Functional analysis clustering of the 78 differentially expressed genes in the consensus heat stress response also identified functional categories of protein folding and regulation of apoptosis. Self-organizing maps identified gene-specific signatures corresponding to protein folding disorders specific to only heat-stressed rats with histopathologic evidence of cardiac injury at 48 hours. Enrichment analysis of differentially expressed proteins in heat-injured hearts at 48 hours corroborated gene enrichment analysis results. Quantitative proteomics analysis by iTRAQ demonstrated that differential protein expression was not comparable to transcript expression at Tc,Max and 24 hours. However, the profile of differentially expressed proteins closely matched the transcriptomic profile in heat-injured animals at 48 hours. Pathway analysis at both the transcript and protein levels supported catastrophic deficits in energetics and cellular metabolism, chronic proteotoxic response, and activation of the unfolded protein response. Calculation of protein super-saturation scores demonstrated an increased propensity of proteins to aggregate in the hearts of heat-injured animals at 48 hours, consistent with accumulation of misfolded proteins. Conclusions: Global transcriptomic and proteomic analysis identified networks of genes and proteins initiating an unfolded protein response, metabolic dysfunction, and mitochondrial energy crisis in animals with histopathologic evidence of persistent heat injury, providing the basis for a systems-level physiological model of heat illness and recovery. To induce the pathophysiological effects of heat stress, conscious rats were placed in an incubator at 37M-BM-:C and their core temperature was monitored. Animals were sacrificed when their core temperature reached 41.8M-BM-:C (Tc,Max), or they were returned to their normal housing environment and were allowed to recover for up to 24 or 48 hours prior to sacrifice. Time-matched controls were euthanized at times corresponding to Tc,Max, 24 hours, and 48 hours. For each condition n=6 for a total of 36 animals. Four tissues (liver, lung, kidney and heart) were analyzed from each animal for a total of 144 arrays; however a few arrays did not pass QC therefore only 140 are reported here: 34 liver, 35 lung, 36 kidney, or 35 heart.

Project description:Korean peninsular weather is rapidly becoming subtropical due to global warming. In summer 2018, South Korea experienced the highest temperatures since the meteorological observations recorded in 1907. Heat stress has a negative effect on Holstein cows, the most popular breed of dairy cattle in South Korea, which is susceptible to heat. To examine physiological changes in dairy cows under heat stress conditions, we analyzed the profiles circulating microRNAs isolated from whole blood samples collected under heat stress and non-heat stress conditions using small RNA sequencing. We compared the expression profiles in lactating cows under heat stress and non-heat stress conditions to understand the regulation of biological processes in heat-stressed cows. Moreover, we measured several heat stress indicators, such as rectal temperature, milk yield, average daily gain, and progesterone concentration. All these assessments showed that pregnant cows were more susceptible to heat stress than non-pregnant cows. Particularly, progesterone concentrations known to have maternal warming effects were at similar levels in non-pregnant cows but significantly increased in pregnant cows under heat stress conditions. The differentially expressed miRNAs and their putative target genes were analyzed in pregnant cows. Interestingly, we found that differentially expressed miRNAs (bta-miR-146b, bta-miR-20b, bta-miR-29d-3p, bta-miR-1246) specifically targeted progesterone biosynthesis (StAR) and the function of corpus luteum-related genes (CCL11, XCL), suggesting that pregnant cows with elevated progesterone concentrations are more susceptible to heat stress. In addition, we found the differential expression of 11 miRNAs (bta-miR-19a, bta-miR-19b, bta-miR-30a-5p, and several from the bta-miR-2284 family) in both pregnant and non-pregnant cows under heat stress conditions. In target gene prediction and gene set enrichment analysis, these miRNAs were found to be associated with the cytoskeleton, cell junction, vasculogenesis, cell proliferation, ATP synthesis, oxidative stress, and immune responses involved in heat response. These miRNAs can be used as potential biomarkers for heat stress.

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Alterations in Tissue microRNA after Heat Stress in the Conscious Rat: Potential Biomarkers of Organ-Specific Injury

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