The integrated stress response in ischemic diseases

Ischemic disease is among the deadliest and most disabling illnesses. Prominent examples include myocardial infarction and stroke. Most, if not all, underlying pathological changes, including oxidative stress, inflammation, and nutrient deprivation, are potent inducers of the integrated stress response (ISR). Four upstream kinases are involved in ISR signaling that sense a myriad of input stress signals and converge on the phosphorylation of serine 51 of eukaryotic translation initiation factor 2 alpha (eIF2 alpha). As a result, translation initiation is halted, creating a window of opportunity for the cell to repair itself and restore homeostasis. A growing number of studies show strong induction of the ISR in ischemic disease. Genetic and pharmacological evidence suggests that the ISR plays critical roles in disease initiation and progression. Here, we review the basic regulation of the ISR, particularly in response to ischemia, and summarize recent findings relevant to the actions of the ISR in ischemic disease. We then discuss therapeutic opportunities by modulating the ISR to treat ischemic heart disease, brain ischemia, ischemic liver disease, and ischemic kidney disease. Finally, we propose that the ISR represents a promising therapeutic target for alleviating symptoms of ischemic disease and improving clinical outcomes.

Automated summary

Ischemic diseases, such as myocardial infarction and stroke, are among the deadliest and most disabling illnesses. The integrated stress response (ISR) plays a critical role in the pathogenesis and progression of ischemic diseases, making it a promising therapeutic target for alleviating symptoms and improving clinical outcomes of ischemic diseases such as ischemic heart disease, brain ischemia, ischemic liver disease, and ischemic kidney disease.