microRNAs a critical factor in cerebral, renal, and cardiovascular ischemia

MicroRNAs are approximately 22 nucleotide long, noncoding RNAs that extensively mediate post-transcriptional gene expression.  They control cellular function by either degrading mRNAs or arresting their translation. MicroRNAs are involved in various critical functions, including the regulation of cellular differentiation, proliferation, angiogenesis, and apoptosis as well as (patho)physiologic conditions such as tumor progression/regression and cholesterol/glucose homeostasis. More recent studies show that microRNAs play a critical role in the response to cerebral, renal, and cardiovascular ischemia and have potential to act as biomarkers of these pathologies and even potential as a therapeutic agent to correct them.

The brain is particularly vulnerable to ischemia, which is accompanied by substantial alterations in gene expression. There is evidence that suggests that several microRNAs may be involved in regulating the normal physiological activity of the brain and its response to ischemia and reperfusion. Researchers across the globe have employed microarray expression profiling to study microRNA’s extensive mediation of post-transcriptional gene expression. In China, at the Zhejiang University School of Medicine, researchers used microarray analysis to characterize the microRNA expression profile in rat hippocampus and to identify changes in expression after global ischemia followed by reperfusion1. They found 23 microRNAs were upregulated and 32 were downregulated. In the USA, at University of Wisconsin, neuroscientists found 17 microRNAs that showed >5 fold change in expression after transient middle cerebral artery occlusion (MCAo) and reperfusion2. The altered microRNAs are correlated to several mRNAs known to mediate inflammation, transcription, neuroprotection, receptors function, and ionic homeostasis. In Singapore, at the National University, scientists also used oligonucleotide microarray to profile microRNA expression from the brain and blood of rats subjected to MCAo and reperfusion3. The data were validated by quantitative real-time polymerase chain reaction and correlate with published data on protein and gene expression in MCAo rats.

Renal ischemia reperfusion injury (IRI) is associated with significant morbidity and mortality. Researchers at Harvard Medical School examined microRNA expression profiles in mouse kidneys following renal IRI and were able to define a molecular fingerprint of renal injury4. In vitro studies revealed that miR-21 is expressed in proliferating tubular epithelial cells (TEC) and up-regulated by ischemia. In vitro knockdown of miR-21 in TEC resulted in increased cell death suggesting that miR-21 may play a role in protecting TEC from death.

There has been significant attention paid to microRNA’s role in cardiovascular health and a recent study by researchers at Stanford University School of Medicine set out to determine if microRNA could be used in a therapeutic role to rescue heart function from ischemic heart disease5. Using microRNA microarrays, they first showed that microRNA-210 was highly expressed in mouse cardiomyocytes compared with apoptotic cells after 48 hours of hypoxia exposure. Taking gain-of-function and loss-of-function approaches they demonstrated that microRNA-210 can improve angiogenesis, inhibit apoptosis, and improve cardiac function in a murine model of myocardial infarction and that it represents a potential novel therapeutic approach for treatment of ischemic heart disease.

1.       Yuan Y, Wang JY, Xu LY, Cai R, Chen Z, Luo BY. (2010) MicroRNA expression changes in the hippocampi of rats subjected to global ischemia. J Clin Neurosci 17(6), 774-78. [abstract]

2.       Dharap A, Bowen K, Place R, Li LC, Vemuganti R. (2009) Transient focal ischemia induces extensive temporal changes in rat cerebral microRNAome. J Cereb Blood Flow Metab 29(4), 675-87. [abstract]

3.       Jeyaseelan K, Lim KY, 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), 959-66. [abstract]

4.       Godwin JG, Ge X, Stephan K, Jurisch A, Tullius SG, Iacomini J. (2010) Identification of a microRNA signature of renal ischemia reperfusion injury. Proc Natl Acad Sci USA 107(32), 14339-44. [abstract]

5.       Hu S, Huang M, Li Z, Jia F, Ghosh Z, Lijkwan MA, Fasanaro P, Sun N, Wang X, Martelli F, Robbins RC, Wu JC. (2010) MicroRNA-210 as a novel therapy for treatment of ischemic heart disease. Circulation 122(11 Suppl), S124-31. [abstract]

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