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Pharmacologic ATF6 activation confers global protection in widespread disease models by reprograming cellular proteostasis.

Blackwood EA, Azizi K, Thuerauf DJ, Paxman RJ, Plate L, Kelly JW, Wiseman RL, Glembotski CC
Nat Commun. 2019 10 (1): 187

PMID: 30643122 · PMCID: PMC6331617 · DOI:10.1038/s41467-018-08129-2

Pharmacologic activation of stress-responsive signaling pathways provides a promising approach for ameliorating imbalances in proteostasis associated with diverse diseases. However, this approach has not been employed in vivo. Here we show, using a mouse model of myocardial ischemia/reperfusion, that selective pharmacologic activation of the ATF6 arm of the unfolded protein response (UPR) during reperfusion, a typical clinical intervention point after myocardial infarction, transcriptionally reprograms proteostasis, ameliorates damage and preserves heart function. These effects were lost upon cardiac myocyte-specific Atf6 deletion in the heart, demonstrating the critical role played by ATF6 in mediating pharmacologically activated proteostasis-based protection of the heart. Pharmacological activation of ATF6 is also protective in renal and cerebral ischemia/reperfusion models, demonstrating its widespread utility. Thus, pharmacologic activation of ATF6 represents a proteostasis-based therapeutic strategy for ameliorating ischemia/reperfusion damage, underscoring its unique translational potential for treating a wide range of pathologies caused by imbalanced proteostasis.

MeSH Terms (25)

Activating Transcription Factor 6 Animals Animals, Newborn Cells, Cultured Cerebral Infarction Disease Models, Animal Endoplasmic Reticulum Female Heart Ventricles Humans Kidney Kidney Diseases Male Mice Mice, Inbred C57BL Mice, Knockout Myocardial Infarction Myocytes, Cardiac Primary Cell Culture Protective Agents Proteostasis Rats Reperfusion Injury Treatment Outcome Unfolded Protein Response

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