Whole genome transcriptomic reveals heat stroke molecular signatures in humans

Author:

Bouchama Abderrezak1ORCID,Rashid Mamoon2,Malik Shuja Shafi1,Al Mahri Saeed1,Yassin Yara3,Abdullah Mashan1,Abdulmalek Nour3,Maashi Fuad3,Mashi Abdulaziz3,Khan Altaf2,Alotaibi Badriah3,Lehe Cynthia1,Mohammad Sameer1,Alkadi Haitham4,Alwadaani Deemah4,Yezli Saber5

Affiliation:

1. Department of Experimental Medicine, King Abdullah International Medical Research Center/King Saud bin Abdulaziz University for Health Sciences Ministry of National Guard Health Affairs Riyadh Saudi Arabia

2. Department of Biostatistics and Bioinformatics, King Abdullah International Medical Research Center/King Saud bin Abdulaziz University for Health Sciences Ministry of Health Affairs of the National Guard Riyadh Saudi Arabia

3. The Global Center for Mass Gathering Medicine Ministry of Health Riyadh Saudi Arabia

4. Department of Medical Genomics, King Abdullah International Medical Research Center/King Saud bin Abdulaziz University of Health Sciences Ministry of Health Affairs of the National Guard Riyadh Saudi Arabia

5. Biostatistics, Epidemiology, and Scientific Computing Department King Faisal Specialist Hospital and Research Centre Riyadh Saudi Arabia

Abstract

AbstractAn 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 the whole 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°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. imageKey points Most living species, including humans, have inherent heat stress response (HSR) that shields them against heat‐induced macromolecular damage. The role of the HSR in subjects exposed to environmental heat who progressed to heat stroke versus those that did not is unknown. Our findings suggest that heat stroke induces a broad and robust HSR of nearly half of the total heat shock proteins, cochaperones, and chaperonin genes. Heat stroke patients exhibited inhibition of genes involved in energy production, including oxidative phosphorylation and ATP production. Significant enrichment of neurodegenerative pathways, including amyloid processing signalling, the Huntington's and Parkinson's disease signalling suggestive of brain proteotoxicity was noted. The data suggests that more than a powerful HSR may be required to protect against heat stroke. Overwhelming proteotoxicity and energy failure might contribute to its pathogenesis.

Publisher

Wiley

Subject

Physiology

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