DOI: 10.1016/j.bbrc.2019.04.161
Ischemic stroke, identified as one of the leading causes of death and disability worldwide, has long been a subject of intense research. The complexity of the brain and the intricacies of its vascular system make it a challenging field for breakthroughs. However, a new study published in “Biochemical and Biophysical Research Communications” has shed light on the role of a long non-coding RNA, known as CHRF, in the modulation of ischemic stroke progression through the miR-126/SOX6 signaling pathway.
Researchers Gai Hai-Yun from the Department of Encephalopathy at Xi’an Hospital of Traditional Chinese Medicine, Wu Chen from the Department of Neurology at Xinjiang PLA Urumqi General Hospital, Zhang Yan from the Department of Acupuncture Rehabilitation at Xi’an Hospital of Traditional Chinese Medicine, and Wang Dong from the Department of Third Neurology at The Second Affiliated Hospital of Xi’an Medical University, conducted both in vivo and in vitro analyses to explore the potential therapeutic applications of these genetic interactions.
The Damaging Effects of Cerebral Ischemia/Reperfusion Injury
Cerebral Ischemia/Reperfusion (I/R) injury is a particularly harmful aspect of ischemic stroke, occurring when blood flow returns to the brain after a period of ischemia, or lack of oxygen due to a blockage. This return can actually cause additional damage, not unlike the injury that might occur when restoring power too quickly after a blackout.
Long Non-Coding RNA CHRF as a Modulator in Ischemic Stroke
CHRF, or cardiac hypertrophy-related factor, was initially studied concerning cardiac injury and various cancers. Its role in ischemic stroke was less clear until this groundbreaking study found that not only is CHRF expression increased in the ischemic core following ischemia, but its levels are inversely related to the expression of miR-126 — a microRNA known to be implicated in vascular inflammation and remodeling.
The Interplay of miR-126 and SOX6
Crucial to this study is the relationship between miR-126 and SOX6 (Sex-determining region Y box 6). miR-126 has been noted to reduce oxygen-glucose deprivation and reoxygenation (OGD/R)-triggered apoptosis in neuronal cells, essentially protecting them from death following ischemic stroke. Apoptosis, or programmed cell death, is a key factor in the damage caused by ischemic stroke.
The study demonstrated that CHRF acts as a competing endogenous RNA (ceRNA) for miR-126, essentially “competing” with SOX6 to bind to miR-126. Through this binding, CHRF influences the regulatory effects of miR-126 on ischemic neuronal death.
The Impact of CHRF Knockdown
In the study, knocking down the expression of CHRF in mice models of ischemic stroke revealed profound protective effects. Mice with reduced CHRF levels demonstrated both a quantitative reduction in ischemic damage, observed through imaging and histological analyses, and a qualitative improvement in neurological functions. This was assessed through locomotion testing and maze learning — two behavioral assessments that indicate neurological status after stroke.
Future Therapeutic Approaches Against Cerebral Ischemic Stroke
The potential for developing new therapies for ischemic stroke is one of the most exciting prospects of this study. The research suggests that manipulating levels of CHRF, or intervening in the CHRF/miR-126/SOX6 signaling pathway, may provide new strategies for therapies to protect against neuronal injury in ischemic stroke.
Broader Implications for lncRNA Research
While this study focuses on a specific lncRNA associated with ischemic stroke, its broader implications should not be overlooked. lncRNAs, once considered “junk” DNA with no functional value, have now emerged as critical regulatory molecules in a variety of biological processes and diseases. The understanding of how these lncRNAs operate and interact with other genetic materials continues to restructure our approach to gene therapy and personalized medicine.
Recommendations and Concluding Thoughts
The practical implications of these research findings pave the way for significant advancements in stroke treatment and recovery. With further exploration and validation of these genetic pathways, it could be possible to reduce the extensive damage caused by ischemic strokes, improving quality of life and outcomes for stroke patients globally.
References
1. Gai, H. Y., Wu, C., Zhang, Y., & Wang, D. (2019). Long non-coding RNA CHRF modulates the progression of cerebral ischemia/reperfusion injury via miR-126/SOX6 signaling pathway. Biochemical and Biophysical Research Communications, 514(2), 550-557. doi:10.1016/j.bbrc.2019.04.161
2. Memczak, S., et al. (2013). Circular RNAs are a large class of animal RNAs with regulatory potency. Nature, 495(7441), 333–338. doi:10.1038/nature11928
3. Jeyaseelan, K., Lim, K. Y., & Armugam, A. (2008). MicroRNA Expression in the Blood and Brain of Rats Subjected to Transient Focal Ischemia by Middle Cerebral Artery Occlusion. Stroke, 39(3), 959-966. doi:10.1161/STROKEAHA.107.500736
4. Small, E. M., & Olson, E. N. (2011). Pervasive roles of microRNAs in cardiovascular biology. Nature, 469(7330), 336–342. doi:10.1038/nature09783
5. Wahlestedt, C. (2013). Targeting long non-coding RNA to therapeutically upregulate gene expression. Nature Reviews Drug Discovery, 12(6), 433-446. doi:10.1038/nrd4018
Keywords
1. Ischemic Stroke Treatment
2. lncRNA CHRF
3. miR-126 SOX6 Signaling
4. Neuronal Apoptosis Prevention
5. Gene Therapy Stroke