The Use of microRNAs to Modulate Redox and Immune Response to Stroke

Abstract

Significance: Cerebral ischemia is a major cause of death and disability throughout the world, yet therapeutic options remain limited. The interplay between the cellular redox state and the immune response plays a critical role in determining the extent of neural cell injury after ischemia and reperfusion. Excessive amounts of reactive oxygen species (ROS) generated by mitochondria and other sources act both as triggers and effectors of inflammation. This review will focus on the interplay between these two mechanisms. Recent Advances: MicroRNAs (miRNAs) are important post-transcriptional regulators that interact with multiple target messenger RNAs coordinately regulating target genes, including those involved in controlling mitochondrial function, redox state, and inflammatory pathways. This review will focus on the regulation of mitochondria, ROS, and inflammation by miRNAs in the chain of deleterious intra-and intercellular events that lead to brain cell death after cerebral ischemia. Critical Issues: Although pretreatment using miRNAs was effective in cerebral ischemia in rodents, testing treatment after the onset of ischemia is an essential next step in the development of acute stroke treatment. In addition, miRNA formulation and delivery into the CNS remain a challenge in the clinical translation of miRNA therapy. Future Directions: Future research should focus on post-treatment and potential clinical use of miRNAs. Antioxid. Redox Signal. 22,[187][188][189][190][191][192][193][194][195][196][197][198][199][200][201][202]

Regulation of multidrug resistance by microRNAs in anti-cancer therapy

“…Several recent studies have shown the regulatory role of miRNA on redox systems176, 177. However, such a role in the field of cancer MDR has not been fully studied.…”

microRNAs affect BCL-2 family proteins in the setting of cerebral ischemia

“…miRNAs bind to messenger RNAs (mRNAs), known as their targets, based on sequence complementarity and direct the degradation or repression of translation of the targeted mRNAs. Recent evidence increasingly supports a role for miRNAs in response to cerebral ischemia, as we have reviewed recently (Ouyang et al, 2013a; Ouyang et al, 2013b). Numerous miRNAs target BCL-2 family proteins.…”

Role of Astrocytes in Delayed Neuronal Death: GLT-1 and its Novel Regulation by MicroRNAs

“…The most common mechanism is for miRNAs to bind to messenger RNAs (mRNAs), known as their targets, based on sequence complementarity and direct the degradation or repression of translation of the targeting mRNAs. Recent evidence increasingly supports a role for miRNAs in response to cerebral ischemia, as we have reviewed recently (Ouyang et al, 2013b; Ouyang et al, 2013a). The fast post-transcriptional effect of miRNAs, and their ability to simultaneously coordinate regulation of many target genes, suggests that miRNAs may have greater therapeutic potential as candidates for the treatment of stroke than therapies targeting a single gene by direct transcriptional control.…”

“…Recently, miR-181a was shown to directly target molecular chaperone GRP78 (Ouyang et al, 2012b), anti-apoptotic members of the BCL2 family BCL2 and myeloid cell leukemia (MCL) 1 (Ouyang et al, 2012a), and X-linked inhibitor of apoptosis (XIAP) (Hutchison et al, 2013) as well as some target proteins involved in controlling mitochondrial function, redox state, and inflammatory pathways (for recent reviews see Ouyang and Giffard (2013); Ouyang et al (2013b)). Although miR-181a antagomir reduces miR-181a levels and significantly inhibits the decrease of GLT-1 after forebrain ischemia, miR-181a does not directly target GLT-1 (Moon et al, 2013).…”